RARE DISEASE
Familial papillary or follicular thyroid carcinoma
Familial papillary or follicular thyroid carcinoma
Familial papillary or follicular thyroid carcinoma
Synonyms: FNMTC, Familial pure nonmedullary thyroid carcinoma
Synonyms: FNMTC, Familial pure nonmedullary thyroid carcinoma
Synonyms: FNMTC, Familial pure nonmedullary thyroid carcinoma
Drug discovery
5
drugs
With orphan designations
Overview
Familial papillary or follicular thyroid carcinoma (FNMTC) is a hereditary subtype of non-medullary thyroid cancer, accounting for 3-10% of cases. It exhibits aggressive features such as multifocality, lymph node metastasis, and higher recurrence rates compared to sporadic cases. Diagnosis requires ≥3 first-degree relatives with follicular-derived thyroid cancer or ≥2 with papillary carcinoma (WHO 2022 criteria) [1][3][5]. Genetic mechanisms remain uncharacterized, necessitating vigilant clinical monitoring.
Burden
Higher rates of extrathyroidal extension (13% vs 0%) and nodal metastasis (33% vs 2% central nodes) [1][7].
Global incidence rising, with disproportionate mortality in low-resource regions due to delayed detection [3][11].
Requires 69% total thyroidectomies vs 4% in sporadic cases, increasing surgical complexity/hormone dependence [1][12].
Therapies
Categories: rare endocrine diseases, rare genetic diseases, rare neoplastic diseases
Research Papers
1,377 drug discovery papers about Familial papillary or follicular thyroid carcinoma, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,377 drug discovery papers about Familial papillary or follicular thyroid carcinoma, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-01 | Mechanistic and Clinical Perspectives on Traditional Chinese Medicine in Thyroid Cancer Management.
Thyroid cancer is one of the most prevalent malignancies of the endocrine system, comprising various subtypes such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and the aggressive anaplastic thyroid carcinoma (ATC). Despite a generally favorable prognosis for PTC, recurrence, metastasis, and resistance to conventional therapies continue to pose significant challenges. The pathogenesis of thyroid cancer involves genetic mutations in BRAF, RAS, and RET, as well as dysregulated molecular pathways such as MAPK, PI3K/Akt/mTOR, and NF-κB, all of which contribute to cancer progression and therapeutic resistance. This review highlights how Traditional Chinese Medicine (TCM), with its extensive history and a diverse range of bioactive compounds derived from natural sources, offers a complementary approach to thyroid cancer treatment. TCM has been shown to modulate various cellular mechanisms, including inhibiting tumor proliferation, inducing apoptosis, and regulating immune responses. Additionally, TCM can influence the tumor microenvironment (TME), reducing immune evasion and improving therapeutic sensitivity. Many TCM compounds have been identified for their ability to target critical oncogenic signaling pathways, offering a holistic approach to cancer treatment with fewer side effects than traditional chemotherapy. Furthermore, integrating TCM with modern medicine, including novel formulations and nanotechnology, offers the potential to improve efficacy and reduce side effects. The convergence of Artificial Intelligence (AI) and Systems Biology also holds great promise for optimizing personalized treatment regimens and advancing targeted therapies, ultimately improving patient outcomes in thyroid cancer management.
2026-08-27 | ERK Signaling in Thyroid Cancer: Lineage Suppression, Epigenetic Reprogramming, and Theranostic Reversal.
Differentiated thyroid carcinoma is a morphologic diagnosis, not a direct measure of preserved thyroid function. Although most papillary, follicular, and oncocytic thyroid carcinomas retain architectural or cytologic features of follicular-cell derivation, a clinically important subset loses the molecular machinery required for effective iodine transport, organification, and radioiodine therapy. This functional divergence is central to the biology of radioiodine-indifferent and radioiodine-refractory thyroid cancer. This review examines the role of oncogenic MAPK/ERK signaling as a principal regulator of thyroid lineage suppression and therapeutic failure. Aberrant activation of the RAF-MEK-ERK axis, most prominently through BRAF^V600E, RAS alterations, and receptor tyrosine kinase fusions, does more than promote proliferation. It reshapes follicular-cell identity by repressing thyroid-lineage transcriptional programs and silencing iodine-handling genes, including SLC5A5/NIS, TPO, TG, TSHR, SLC26A4, and related components of the iodine metabolic transcriptome. This repression is mediated through coordinated transcriptional, epigenetic, and post-transcriptional mechanisms involving lineage transcription factors such as PAX8, NKX2-1, and FOXE1; chromatin-modifying programs including histone deacetylation and PRC2/EZH2-associated repression; DNA methylation; and non-coding RNA networks. Importantly, ERK-driven functional dedifferentiation is not always a fixed terminal state. Preclinical models and early clinical trials demonstrate that pharmacologic inhibition of the MAPK pathway can restore iodine avidity in selected radioiodine-refractory tumors, creating the theranostic basis for redifferentiation therapy. Iodine-124 PET/CT and lesion-level dosimetry have shown that restored iodine uptake can be measured diagnostically and then exploited therapeutically with iodine-131. However, clinical translation remains limited by inter- and intratumoral heterogeneity, incomplete durability of response, adaptive pathway reactivation, persistent epigenetic repression, tumor microenvironmental influences, and the absence of standardized dosimetric thresholds. We propose that advanced follicular-cell-derived thyroid cancers should be understood along a functional differentiation continuum rather than through morphology alone. Within this framework, radioiodine refractoriness reflects not merely treatment failure, but a therapeutically interrogable state of lineage suppression. Refinement of redifferentiation therapy will require genotype-informed patient selection, functional imaging, standardized dosimetry, rational combination strategies, and prospective trials capable of distinguishing true restoration of radioiodine therapeutic efficacy from the antiproliferative effects of kinase inhibition alone.
2026-07-23 | Autophagy in thyroid cancer: stage-dependent switch, mutation-specific regulation, and therapeutic targeting.
Autophagy plays context-dependent roles in thyroid cancer, but whether its dual nature represents a reversible balance or an irreversible stage-dependent switch has remained unclear. This review synthesizes evidence across papillary, follicular, medullary, and anaplastic thyroid carcinoma subtypes and reveals that the transition from tumor-suppressive to tumor-promoting autophagy is unidirectional and driven by disease progression, not a simultaneous equilibrium. The major driver mutations BRAF V600E, RAS, and RET regulate autophagy through distinct mechanisms, demanding subtype-specific therapeutic strategies rather than a uniform approach. Importantly, autophagy is an adaptive resistance mechanism rather than a primary driver, as no thyroid cancer is driven by mutations in autophagy genes. Consequently, autophagy inhibitors will not work as monotherapy but may sensitize tumors to standard treatments that create therapeutic stress. Current clinical translation remains stalled by poor inhibitor specificity, lack of validated biomarkers, and unknown treatment timing. We conclude that the field should move from descriptive studies to biomarker-enriched, hypothesis-driven trials, prioritizing anaplastic thyroid carcinoma for hydroxychloroquine-TKI combinations while standardizing assays for p62 and LC3B to enable patient selection.
2026-06-22 | Multidisciplinary treatment of follicular thyroid carcinoma with hepatic and pulmonary metastases: a case report and literature review.
To determine the clinical diagnostic features, molecular basis, and comprehensive treatment strategies for a case of follicular thyroid carcinoma (FTC) with hepatic and pulmonary metastases that developed 8 years after surgery for a Follicular Tumor of Uncertain Malignant Potential (FT-UMP), and to provide a basis for long-term follow-up and individualized treatment of such borderline tumors. FTC is the second most common subtype of differentiated thyroid cancer. Currently, the diagnosis and management of distant FTC metastases remain a critical challenge, particularly when they occur in rare locations, such as the liver. This article reports the case of a 56-year-old male patient. Within 8 years after the resection of the well-differentiated follicular neoplasm of FT-UMP, a single mass in the lateral lobe of the left liver and multiple nodules in both lungs were detected in the patient. Following a multidisciplinary team (MDT) discussion, the decision was made to perform a robot-assisted hepatectomy. Pathology confirmed the diagnosis of FTC metastasis. Subsequently, we formulated a comprehensive treatment plan including total thyroidectomy, radioactive iodine (RAI) therapy with 131I and endocrine treatment. Active surveillance was adopted for the lung metastases. Twelve months of follow-up showed no signs of recurrence. This case highlights that for patients with FT-UMP, continuous monitoring is also crucial for the early detection of metastasis. In complicated cases with liver and lung metastases from FTC, MDT collaboration is essential to formulate individualized treatment plans integrating multidisciplinary expertise and multimodal therapies.
2026-06-08 | Pathology-based thermal ablation safety margin for follicular adenoma: a digital whole-slide study of follicular carcinoma invasion.
Follicular adenoma (FA) and follicular thyroid carcinoma (FC) are difficult to differentiate before surgery, raising concerns that thermal ablation (TA) of FA might treat an occult minimally invasive FC. Therefore, the microscopic extent of FC invasion was quantified to propose a pathology-informed ablation safety margin. A retrospective analysis was conducted on 43 surgically resected FCs treated between 2016 and 2023. Two readers independently reviewed the pathological images (×40 magnification). The capsule infiltration distance (the maximum depth of infiltration beyond the capsule) and the minimally invasive infiltration distance (the ultrasound-undetectable occult infiltration depth) were measured. These distances were compared by tumor stage, FC pathological classification, and lymph node metastasis (LNM). The capsule infiltration distance ranged from 0.14 to 6.10 mm (mean, 1.49 ± 1.22). The minimally invasive infiltration distance ranged from 0.09 to 1.36 mm (mean, 0.56 ± 0.37). The distances did not differ by tumor stage, FC pathological classification, sex, or lymph node metastasis (LNM) (all P > 0.05). Age was associated with a larger capsule infiltration distance (P = 0.040). However, age was not associated with the minimally invasive infiltration distance (P = 0.367). The minimally invasive infiltration in FC did not exceed 1.36mm in this cohort. Since the actual ablation area achieved by clinical TA exceeds the pathological margin, this supports the extended ablation safety margin of 2mm beyond the sonographic tumor boundary. This TA margin could cover occult minimally invasive FC.
proteins
2025-09-04 | Identification of BCL2L11 as a Candidate Gene for Hereditary Predisposition to Non-Medullary Thyroid Cancer Using Familial Whole-Exome-Sequencing.
Familial non-medullary thyroid cancer, defined as two or more affected first-degree relatives, accounts for 3%-9% of thyroid cancers. It is associated with more aggressive cancer, early age at diagnosis, multifocality, and increased risk of metastasis and recurrence. Although no high penetrance predisposing gene has been identified at present, the estimated contribution of genetics is significant. Our study explored five families presenting FNMTC using Whole-Exome Sequencing and found three candidate genes: TELO2 in one family, UACA and BCL2L11 in another. All of these tumor suppressor genes are expressed in the thyroid, exhibit under-expression in tumor tissue compared to healthy tissue both in silico and in our samples, and two of them are known to be involved in thyroid carcinogenesis via the FOXO3A pathway. Functional analysis to validate these candidate genes in thyroid cancer cells showed that one of the three, BCL2L11, has a tumor suppressor effect on proliferation and apoptosis. Their impact on hereditary predisposition to thyroid cancer, as well as their combined effects, requires further study. Indeed, a case-control study would be essential to determine the diagnostic utility of their routine analysis.
2025-07-17 | ANTP-SmacN7 enhances radiosensitivity in TPC-1 cells through XIAP-mediated activation of apoptotic protein.
A subset of differentiated thyroid cancer still lacks effective treatment options, such as locally advanced or metastatic patients. Some of these patients also need to try radiation therapy. The objective of this study is to investigate the potential of the antennapedia-modified SMAC fragment (ANTP-SmacN7) as a radiation sensitizer to enhance the therapeutic efficacy of radiotherapy in papillary carcinoma of thyroid (PTC), ascertain the contribution of X-linked inhibitor of apoptosis protein (XIAP), and explore its associated mechanisms to the apoptotic response in PTC. Methods To determine whether ANTP-SmacN7 enhances radiotherapy sensitivity by promoting apoptosis through XIAP in thyroid cancer, we first performed bioinformatics analysis of XIAP in thyroid cancer (THCA) using TCGA/GTEx THCA datasets. This analysis evaluated XIAP expression levels, its correlation with clinical pathological features and prognosis, functional enrichment, and interactions with apoptosis-related genes of CASP. Subsequently, we treated TPC-1 cells with gamma ray and ANTP-SmacN7 in different groups and assessed cell proliferation, migration, and apoptosis-related protein expression (XIAP, caspase-3, caspase-8, and caspase-9) using CCK-8, colony formation, transwell assays, annexin V/PI double staining, and western blotting. To further elucidate the role of XIAP and the effects of ANTP-SmacN7, we constructed XIAP-overexpressing TPC-1 cells, treated them with gamma ray and ANTP-SmacN7 in different groups, and compared changes of cell function and apoptosis-related protein. XIAP is highly expressed in THCA and demonstrates significant correlations with aggressive clinicopathological features including advanced T stage (p = 0.018) and extrathyroidal extension (p = 0.017) in THCA, while its prognostic stratification potential is evidenced by an AUC of 0.63. It interacts closely with CASP family members involved in apoptosis, which might critically inform therapeutic strategies for radioresistant THCA. The experimental results demonstrate that TPC-1 cells are sensitive to low-dose gamma ray but exhibit radioresistant as the radiation dose increases. While ANTP-SmacN7 significantly enhances gamma ray-induced radiosensitization. When combined with gamma ray, ANTP-SmacN7 markedly reduces cell proliferation, viability, and migration, while simultaneously promoting apoptosis. This effect is mediated by XIAP inhibition, which activates the intrinsic apoptosis pathway through caspase-3 and caspase-9. Additionally, XIAP influences the extrinsic apoptosis pathway by directly or indirectly upregulating caspase-8. ANTP-SmacN7 could be a probable candidate for a pharmaceutical radiosensitizer when combined with gamma ray for the treatment of PTC. These findings may provide a theoretical basis for the development of radiosensitization strategies for locally advanced or metastatic patients.
2025-03-17 | Identification of GPX3 and JUN as Tumor Suppressors in Thyroid Cancer through Integrated WGCNA and Mendelian Randomization.
Background: Thyroid cancer (TC) ranks among the most common malignancies globally, with an increasing incidence among younger populations. While papillary thyroid carcinoma (PTC) generally has a favorable prognosis, other forms of TC, such as anaplastic thyroid carcinoma (ATC), are associated with poor outcomes. Although specific mutations, such as BRAFV600E, have been identified in certain types of TC, the underlying mechanisms remain largely unclear. Therefore, there is a critical need to further explore therapeutic targets associated with malignant tumors to improve treatment outcomes. Method: We integrated eQTL data from European populations with RNA-Seq data from TC patients obtained from TCGA and multiple GEO databases. Through differential expression analysis, WGCNA, and Mendelian randomization (MR) analysis, we sought to identify potential gene therapy targets in TC. Additionally, we explored the biological behaviors of these targets using various cellular biology assays, such as MTT, colony formation, wound healing, and Transwell assays. Molecular biology techniques, including Western blot, were employed to investigate the underlying mechanisms. Result: Differential expression analysis across six GEO datasets identified 649 genes associated with TC. Subsequent WGCNA analysis of the GSE6339 dataset revealed 2,739 genes, and MR analysis further identified 189 genes. The intersection of these datasets highlighted four key genes: TIAM1, RAP1GAP, GPX3, and JUN. GO analysis linked these genes to "response to oxidative stress" and "regulation of GTPase activity". KEGG pathway analysis demonstrated significant enrichment in pathways including "Glutathione metabolism", "cAMP signaling pathway", "Rap1 signaling pathway", "Tight junction", and "Thyroid hormone synthesis". Further, single-gene GSEA analyses suggested distinct pathways through which each gene may influence TC progression. Immune profiling revealed marked differences in immune cell populations, notably CD8+ T cells, monocytic lineage cells, neutrophils, NK cells, and T cells, between normal and cancerous thyroid tissues. Notably, RAP1GAP, GPX3, and JUN were implicated in the regulation of Treg and follicular helper T cell functions. The differential expression of these genes was rigorously validated using TCGA dataset and six additional GEO datasets. While the tumor-suppressive roles of TIAM1 and RAP1GAP have been previously established, our findings reveal that the overexpression of GPX3 and JUN significantly impairs the proliferative and migratory capacities of TC cells, underscoring their potential as therapeutic targets. Conclusion: This study identifies GPX3 and JUN as critical tumor suppressor genes in TC, with their function closely linked to T regulatory cells and follicular helper T cells. The overexpression of GPX3 and JUN demonstrates significant tumor-suppressive activity, highlighting their potential as effective therapeutic targets in combating TC.
2024-01-18 | YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling.
N6-Methyladenosine (m6A) mRNA methylation modification is regarded as an important mechanism involved in diverse physiological processes. YT521-B homology (YTH) domain family members are associated with the tumorigenesis of several cancers. However, the role of YTHDC2 in papillary thyroid cancer (PTC) progression remains unknown. Results showed that YTHDC1, YTHDF1, YTHDF2, and YTHDF3 showed no observable difference in thyroid cancer samples. YTHDC2 was significantly downregulated in thyroid cancer samples and cells. YTHDC2 inhibited cell proliferation in PTC cells. YTHDC2 elicited apoptosis in PTC cells, as demonstrated by the elevated expression of pro-apoptotic factors cl-caspase-3/caspase-3 and Bcl-2-associated (Bax), and the reduced anti-apoptotic B cell lymphoma-2 (Bcl-2) expression. There was a positive correlation between YTHDC2 and cylindromatosis (CYLD) expression based on GEPIA database. YTHDC2 increased CYLD expression in PTC cells. CYLD knockdown abolished the effects of YTHDC2 on PTC cell proliferation and apoptosis. Additionally, YTHDC2 inactivated the protein kinase B (Akt) pathway by increasing CYLD in PTC cells. Overall, YTHDC2 inhibited cell proliferation and induced apoptosis in PTC cells by regulating CYLD-mediated inactivation of Akt pathway.
2022-07-28 | USP13 genetics and expression in a family with thyroid cancer.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and its incidence has greatly increased in the last 30 years. Ubiquitin-specific protease 13 (USP13) is a class of deubiquitinating enzymes (DUBs) and plays an important role in cellular functions such as cell cycle regulation, DNA damage repair, and different cell signaling pathways. Studies regarding the role of USP13 in cancer development and progression are divergent and there are no previous data regarding the role of USP13 gene in PTCs. In this study, we investigated the genetic cause of PTC diagnosed in multiple members of a Brazilian family. Whole exome sequencing (WES) was performed to identify the genetic cause of PTC. Cycloheximide chase assay and clonogenic assay were performed to study USP13 stability and function in vitro. WES analysis identified a heterozygous missense variant c.1483G > A (p.V495M) in the USP13 gene that fully segregates with the disease. In silico modeling suggests that this variant may cause protein structural perturbations. USP13 overexpression increased the potential of a single cell to form colonies. The USP13 c.1483G > A variant enhanced the effects seen in USP13 overexpression and preserved protein stability for longer hours compared to the non-mutated USP13 protein. Our study suggests that USP13 overexpression may play a role in tumorigenesis of PTCs; and that the USP13 p.V495M (c.1483G > A) variant enhances USP13 estability.
antibodies
2026-03-02 | Advances in immunotherapy for thyroid malignancies: from molecular targets to clinical outcomes.
Thyroid cancers comprise a diverse collection of endocrine tumors, notably papillary, follicular, medullary, and anaplastic carcinomas, each differentiated by their molecular alterations, clinical behavior, and responsiveness to therapies. Current treatment algorithms of surgical resection, radioiodine treatment, and selective small-molecule inhibitors, although effective for many cases, confront significant limitations, particularly in anaplastic and advanced medullary tumors, where resistance to conventional agents correlates with diminished prognosis, thereby demanding the exploration of innovative therapeutic strategies. This article reviews contemporary immunotherapy-directed interventions for thyroid cancers, highlighting the elucidation of actionable tumor antigens, the reengineering of the immunologic tumor microenvironment, and the ongoing efforts to translate these laboratory findings into practicable, evidence-based clinical protocols. Recent studies underscore the critical efficacy of immune checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 pathways in select populations of anaplastic thyroid carcinoma (ATC), medullary thyroid carcinoma (MTC), and PD-L1-expressing differentiated thyroid cancers. Next-generation immune modulators, specifically inhibitors directed against LAG-3 and TIM-3, are being evaluated in combinatorial frameworks. Vaccines engineered to elicit responses against the BRAF V600E mutation, RET/PTC fusions, and additional neoantigens have shown promising immunogenic profiles in preliminary trial cohorts, while adoptive transfer methodologies, including tumor-infiltrating lymphocyte (TIL) mobilization and engineered CAR-T lymphocytes, are progressing through preclinical and early-phase clinical benchmarks. Concurrently, oncolytic viral vectors are being harnessed to amplify neoantigen liberation and, consequently, to amplify systemic immunity. When immunotherapeutic modalities are judiciously aligned with tyrosine kinase inhibitors (TKIs) or radiotherapeutic regimens, cumulative anti-tumor effects are accentuated, purportedly through mechanisms such as immunogenic cell death induction and the reprograming of immune-tolerant tumor ecosystems. Immunotherapy is set to transform the treatment paradigm for thyroid cancers, although remaining hurdles, the disquietingly low baseline immunogenicity of differentiated tumors, the rapid, capricious emergence of resistance, and complex immune-related endocrine toxicities, must be systematically addressed. Success in this arena will hinge on utilitarian biomarker-based cohort selection, the discovery of fresh immunogenic epitopes, and the meticulous design of synergistic treatment combinations. The synergistic leverage of genomic, transcriptomic, and immune landscape dissection, coupled with cutting-edge engineered lymphocyte platforms and engineered oncolytic vectors, may finally position immunotherapy as an unassailable pillar of bespoke medicine for advanced thyroid carcinomas.
2026-02-22 | Milk fat globule-EGF factor 8 enhances the proliferation and migration of thyroid carcinoma cells through epithelial-mesenchymal transition and PI3K/AKT signaling pathway.
Milk fat globule-EGF factor 8 (MFG-E8) has been found to be involved in the development and progression of several carcinomas. However, the role of MFG-E8 in thyroid carcinoma has not been studied yet. This study aimed to investigate the expression and function of MFG-E8 in thyroid carcinoma (TC). Single-cell RNA sequencing, transcriptome sequencing, mass spectrometry, and immunohistochemistry were used to analyze MFG-E8 expression in papillary thyroid carcinoma (PTC). Western blotting and RT-PCR were performed to assess MFG-E8 expression in TC cell lines. Stable MFG-E8 knockdown cell lines were established, and functional assays were conducted to evaluate the effects of MFG-E8 on TC cell proliferation, migration, and invasion. Bioinformatics analysis and Western blotting were employed to explore the potential downstream signaling pathways. The association between MFG-E8 expression and immune cell infiltration in the tumor microenvironment was also analyzed using bioinformatics tools. MFG-E8 expression was significantly upregulated in PTC tumor tissues. It was closely associated with specific PTC subtypes, with higher expression observed in the tall-cell subtype compared to the classic and follicular subtypes. Knockdown of MFG-E8 significantly inhibited TC cell proliferation, migration, and invasion. Mechanistically, MFG-E8 was found to be associated with the regulation of epithelial-mesenchymal transition (EMT)-related processes and linked to the modulation of the PI3K/AKT signaling pathway in TC cells. Furthermore, MFG-E8 correlated with the formation of an immunosuppressive tumor microenvironment by modulating immune cell infiltration and activating the PI3K/AKT pathway in immune cells. Our findings identify MFG-E8 as a key driver of thyroid carcinoma progression, particularly in aggressive subtypes, and highlight its translational value as a prognostic biomarker and promising therapeutic target by targeting the MFG-E8-PI3K/AKT-EMT axis-providing a new clinical framework for personalized treatment of TC.
2026-02-02 | CXCL8/SDC1 axis mediates tumor stem cell interactions to drive remote transfer in thyroid cancer.
This study explores the molecular mechanisms behind the remote transfer of thyroid cancer (THCA) by investigating the interaction network of C-X-C motif chemokine ligand 8+ (CXCL8+ monocytes and syndecan-1+ (SDC1+) tumor stem cells using single-cell and spatial transcriptome sequencing. Tumor samples from THCA patients were analyzed using single-cell RNA sequencing (scRNA-seq), spatial transcriptome sequencing, and tumor tissue transcriptome analysis. Data were processed with Seurat and CellChat R packages, integrated via the SPOTlight package, and correlated with clinical data from the UCSC Xena database. Functional pathway enrichment analyses were performed using Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genome (KEGG). In vitro, a co-culture system of monocytes and THCA stem cells was developed, and protein levels were measured via enzyme-linked immunosorbent assay (ELISA) and Western blotting. The self-renewal and migration of follicular thyroid carcinoma (FTC) 238-S cells were assessed through sphere formation, colony formation, Cell Counting Kit-8 (CCK-8), and Transwell assays. In vivo, a subcutaneous tumor xenograft model and a lung metastasis model were established in nude mice. Transcriptomic analyses identified the CXCL8/SDC1 axis as a key mediator of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling activation, promoting THCA stem cell self-renewal, invasion, and metastasis. CXCL8/SDC1 expression was significantly higher in the high-risk C1 subtype of THCA patients and correlated with a worse prognosis. In vitro and animal studies confirmed that the CXCL8/SDC1 axis drives tumor progression and metastasis. The interaction between CXCL8+ monocytes and SDC1+ tumor stem cells activates the JAK-STAT pathway, facilitating the remote transfer of THCA. Targeting the CXCL8/SDC1 axis may provide novel therapeutic strategies for improving THCA patient outcomes.
2025-09-22 | Multi-omics analysis and metastasis risk factor prediction in N1b stage PTMC: insights into immune infiltration and therapeutic implications.
Papillary thyroid microcarcinoma (PTMC) with lateral neck lymph node involvement exhibits a deceptively indolent yet highly invasive phenotype, characterized by early dissemination and slow tumor growth. A comprehensive understanding of integrating multiomics landscapes, circulating immune profiles, and tumor immune microenvironment is essential for more accurate surveillance and tailored therapeutic strategies. Clinical profile and circulating immune-inflammatory markers from 638 PTMC patients were analyzed using multivariate and least absolute shrinkage and selection operator (LASSO) regression to recognize N1b-associated risk indicators. Eight supervised machine learning models were trained via 10-fold cross-validation to select the optimal classifier. Weighted gene coexpression network analysis (WGCNA) alongside machine learning identified metastasis-related gene modules from the integrated RNA-seq profile, leading to a multilayer perceptron gene classifier. Genomic profiling was employed to investigate mutations, copy number alterations, and methylation modifications in signature genes, followed by screening of antineoplastic drugs and docking simulations to explore their therapeutic potential. CIBERSORT, combined with immunohistochemistry, was used to investigate immune infiltration and functional changes in N1b-stage PTMC lesions. Two clinical metastasis risk models were developed, with Model A based on the neutrophil-to-lymphocyte ratio (NLR) and Model B on lymphocyte and neutrophil counts, where Model A showed superior generalization (AUC = 0.852) and discriminative performance. NLR was an independent risk determinant for N1b-stage PTMC (OR = 2.12, p < 0.01). Transcriptomic profiling revealed a molecular signature (ALDH1A3, CTXN1, MGAT3, and TMEM163) of occult lateral lymph node metastasis, exhibiting strong robustness (AUC = 0.857). Signature genes were predominantly associated with cell adhesion, intercellular signaling, and KRAS dysregulation pathways. Hypomethylation of CTXN1, MGAT3, and TMEM163 may underlie transcriptional activation. N1b-stage tumors exhibited reduced CD8+ T and T follicular helper cell infiltration but increased dendritic, γδ T, and activated CD4+ memory T cells, suggesting immune evasion and compensatory immune activation. This study constructed a robust metastasis prediction nomogram for N1b-stage PTMC and identified metastasis-associated molecular drivers through integrative multiomics analysis. Comprehensive profiling of systemic and tumor-infiltrating immunity revealed key antitumor immune alterations. These findings establish a framework for early metastatic phenotype detection, potentially inspiring relevant immunotherapeutic hypotheses.
2025-05-21 | Proteomic analysis reveals modulation of key proteins in follicular thyroid cancer progression.
Cytopathology cannot be used to reliably distinguish follicular thyroid adenoma (FTA) from follicular thyroid carcinoma (FTC), the second most common form of thyroid cancer, because they exhibit nearly identical cellular morphology. Given the challenges in diagnosis and treatment, this study aims to identify the mechanisms underlying FTC is essential. Using parallel reaction monitoring-mass spectrometry (PRM-MS) assays, we identified and quantified 94 differentially expressed protein candidates from a retrospective cohort of 1085 FTC and FTA tissue samples from 18 clinical centers. Of these targeted proteins, those with the potential for distinguishing FTC from FTA were prioritized using machine learning. Co-immunoprecipitation (co-IP) and immunofluorescence co-localization assays, as well as gene interference, overexpression, and immunohistochemistry (IHC) experiments, were used to investigate the interactions and cellular functions of selected proteins. Using machine learning models and feature selection methods, 30 of the 94 candidates were prioritized as key proteins. Co-IP and immunofluorescence co-localization assays using FTC cell lines revealed interactions among insulin-like growth factor 2 receptor (IGF2R), major vault protei (MVP), histone deacetylase 1 (HDAC1), and histone H1.5 (H1-5). Gene interference and overexpression experiments in FTC-133 cells confirmed the promotional role of these proteins in cell proliferation. IHC assays of patient samples further confirmed elevated expression of these four proteins in FTC compared with that in FTA. Our findings underscore the utility of advanced proteomic techniques in elucidating the molecular underpinnings of FTC, highlighting the potential significance of IGF2R, MVP, HDAC1, and H1-5 in FTC progression, and providing a foundation for the exploration of targeted therapies.
oligonucleotides
2026-09-16 | Clinical Relevance and Regulatory Mechanisms of LINC01521 in Papillary Thyroid Carcinoma.
Papillary thyroid carcinoma (PTC) is a well-differentiated malignancy derived from thyroid follicular epithelial cells. This study explores the functional role and underlying mechanisms of LINC01521 in PTC, aiming to provide new strategies to improve prognostic assessment and survival rates for PTC. The study cohort comprised 120 patients with PTC. LINC01521 expression in PTC tissues and cells was quantified by qRT-PCR. The association between LINC01521 and PTC malignant progression and adverse prognosis was evaluated by the chi-square test. The target relationship between LINC01521 and miR-4319 was confirmed by the starBase database. The effects of LINC01521 on PTC cell behavior and cuproptosis were examined by CCK8, Transwell, and related kits, and the potential regulatory mechanisms involved were further elucidated. LINC01521 was markedly upregulated in PTC tissues and cells. High LINC01521 expression is closely linked to the malignant clinical features of PTC, including more tumor lesions, increased tumor size, more advanced TNM staging, higher LNM rates, and poorer tumor differentiation. LINC01521 is an independent prognostic risk factor for PTC. Elevated LINC01521 levels indicated shorter overall survival. LINC01521 targets and regulates miR-4319. LINC01521 knockdown led to a significant decrease in the proliferation, migration, and invasion of PTC cells. LINC01521 overexpression attenuated ES + Cu2+ induced cuproptosis, while miR-4319 overexpression reversed these effects. LINC01521 acts as a promising prognostic marker for predicting PTC malignant progression and adverse outcomes. LINC01521 promotes PTC progression by affecting PTC cell function and inhibiting cuproptosis, and the possible regulatory mechanism is through targeting miR-4319.
2024-11-04 | Clinically aggressive follicular cell-derived thyroid carcinoma: A comprehensive series with histomolecular characterization and discovery of novel gene fusions.
Thyroid cancer rates are increasing, mostly with a good prognosis and less than 2 % of cases are more aggressive. Recent efforts focus on understanding molecular events predicting tumor aggressiveness and treatment targets in advanced thyroid cancer. This study concerned 57 patients with aggressive metastatic, and/or radioiodine-refractory thyroid carcinomas, excluding anaplastic cases. Molecular profiling, including next-generation sequencing and RNA sequencing, was conducted to dissect the complex molecular landscape of these aggressive tumors. Histopathological analysis indicated that papillary carcinomas and high-grade thyroid carcinomas were predominant. The molecular analysis revealed a spectrum of mutations, with prevalent occurrences of BRAF V600E, TERT promoter, and RAS mutations. RNA sequencing identified ten gene fusions, such as NTRK and RET fusions. Three novel fusions were discovered: UGGT1::TERT, BTBD9::TERT, and TG::IGF1R, potentially driving aggressive behavior. UGGT1::TERT was linked to radioiodine-refractory tall cell PTC, BTBD9::TERT to high-grade follicular PTC, and TG::IGF1R to oncocytic carcinoma. These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.
2024-07-24 | Oncogenic pseudogene DUXAP10 knockdown suppresses proliferation and invasion and induces apoptosis of papillary thyroid carcinoma cells by inhibition of Akt/mTOR pathway.
Pseudogenes, another novel group of non-coding segments without protein-coding capacity, are closely associated with tumourigenesis and cancer progression. Double homeoboxA pseudogene 10 (DUXAP10) is reported to be robustly expressed in thyroid carcinoma. However, the functional role and underlying mechanism of DUXAP10 in papillary thyroid carcinoma (PTC) progression remain undefined. DUXAP10 expression in PTC cells was detected by qRT-PCR. Cell proliferation and invasion were determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell invasion assay, respectively. Apoptosis was evaluated using flow cytometry. Protein expression of matrix metalloproteinase (MMP)-2, MMP-9, protein kinase B (Akt), phosphorylated Akt, mammalian target of rapamycin (mTOR), and phosphorylated mTOR was examined by western blot. Results showed that DUXAP10 was significantly overexpressed in PTC cells compared with normal thyroid follicular epithelium cells. DUXAP10 silencing suppressed cell proliferation and invasive ability, reduced the expression of MMP-2 and MMP-9, and increased apoptotic rate and caspase-3 activity in PTC cells. Additionally, the Akt/mTOR pathway was inhibited following DUXAP10 knockdown in PTC cells. Activation of the Akt/mTOR pathway by 740Y-P and MHY1485 attenuated DUXAP10 knockdown-induced proliferation reduction, invasion suppression and apoptosis in PTC cells. In conclusion, DUXAP10 knockdown suppressed proliferation and invasion and induced apoptosis in PTC cells at least partially by inhibition of the Akt/mTOR pathway.
2024-03-08 | Translocated HMGB3 is involved in papillary thyroid cancer progression by activating cytoplasmic TLR3 and transmembrane TREM1.
The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.
2024-03-04 | Spatial transcriptomics reveals prognosis-associated cellular heterogeneity in the papillary thyroid carcinoma microenvironment.
Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.
other
2026-06-19 | MCM2 germline variants predispose to familial papillary thyroid carcinoma due to genomic instability caused by MCM complex disruption.
In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a hereditary subtype for which large-scale clinical cohort studies are lacking and definitive susceptibility genes remain elusive. A large fPTC clinical cohort (171 cases), 490 sporadic papillary thyroid carcinoma (sPTC) patients, and 500 healthy blood samples from physical examination were collected in the study. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were used to screen for susceptibility genes. Three MCM2 gene mutations (c.1092 C > G, p.N364K; c.1975A>G, p.I659V; and c. 2379 G > A, p.M793I) in 8 patients from 4 distinct families were identified as candidate susceptibility variants. These mutations disrupt the interaction of MCM2 with its partner proteins (MCM3-7), leading to ubiquitination of free MCM monomers. Levels of DNA damage, γ-H2AX foci, RPA foci, and micronucleus formation were significantly elevated in MCM2-deficient cells. Cell-derived xenograft (CDX) modeling, combined with WES and RNA-seq analyses, revealed that MCM2-deficient tumors exhibited significantly faster growth rates and increased chromosomal instability (CIN). MAPK signaling and the PI3K-AKT pathway were significantly over-activated in MCM2-deficient tumors. In our study, based on the fPTC cohort, germline variants of MCM2 predispose to fPTC. The variants disrupt the MCM complex, leading to ubiquitination of free monomeric MCM proteins. MCM2 deficiency induces cell cycle arrest, DNA damage, and CIN, ultimately accelerating tumorigenesis through oncogenic pathway activation. These findings identify MCM2 as a low-frequency, moderately penetrant susceptibility gene for fPTC and underscore the clinical value of MCM2 testing in informing early detection, preventive management, and precision treatment strategies for familial papillary thyroid carcinoma.
2025-11-23 | Tumor-infiltrating T Lymphocytes Recognize Thyroid-specific Proteins and Neo-antigens in Follicular Cell-derived Thyroid Cancers.
Thyroid cancers are among the growing list of cancer types that are resistant to immune-checkpoint inhibitor monotherapy. Although T-cell infiltration is common in follicular cell-derived thyroid cancers, tumor mutation burden is low. The antigenic potential of thyroid cancers is unknown. To investigate the anti-tumor T-cell response in thyroid cancer, we expanded tumor-infiltrating lymphocytes (TIL) from primary thyroid tumors and tumor-involved lymph nodes (TILN). Putative neoantigens and both tissue-associated and tumor-associated antigens were identified by targeted sequencing and RNA-seq. HLA typing was performed for all patients, and neoantigen binding potential was predicted for each patient using NetMHCpan 4.1 and NetMHCIIpan 4.0 algorithms. In parallel, T-cell receptor β sequencing was performed to detect T-cell clonal expansions in patient-matched primary tumors and TILN. TIL reactivity to tumor-associated antigens and neoantigens was determined in vitro by interferon γ ELISA and flow cytometry. Tumor-infiltrating T cells were evident in all thyroid tumors and readily expanded ex vivo. Shared clones were present in primary thyroid tumors and matched TILN in all patients tested, constituting 1% to 10% of the sequenced clones in 6/8 patients. T-cell reactivity to thyroid tissue-specific proteins, thyroid peroxidase and thyroglobulin, was observed in 84.6% (11/13) and 69.2% (9/13) patients, respectively. A BrafV600E-specific T-cell response was evident in 80% (4/5) BrafV600E+ patients. T cells reactive to gene fusion-derived neoantigens were detected in patients with TPR-NTRK1+ and CCDC6-RET+ thyroid cancer. Our studies confirm the presence of tumor antigen-specific T cells in patients with thyroid cancer and encourage further exploration of T cell-targeted immunotherapies for patients with progressive, treatment refractory thyroid cancer.
2025-06-12 | Overexpression of decorin gene influences the biological behaviors of follicular thyroid carcinoma cells.
The objective of the present study was to examine the impact of decorin (DCN) gene overexpression on the proliferation, migration and invasion of human follicular thyroid carcinoma (FTC) cells. DCN expression was evaluated by western blotting (WB) in Nthy-ori3-1 normal thyroid cells and in two FTC cell lines, namely FTC-133 and FTC-238. Lentiviral transfection was employed to overexpress DCN in the FTC cells, with the overexpression efficiency confirmed through reverse transcription-quantitative polymerase chain reaction and WB. Cell viability, colony formation, wound healing and Transwell invasion assays were conducted to assess the proliferation, migration and invasion of the transfected cells. The results revealed that DCN expression in FTC-133 and FTC-238 cells was significantly lower compared with that in Nthy-ori3-1 cells. Successful lentiviral overexpression of DCN in the FTC cell lines significantly decreased the proliferation and colony formation abilities of the cells, and diminished their wound healing and invasive capabilities. This indicated that the lentivirus-mediated overexpression of DCN in FTC-133 and FTC-238 cells altered their cellular behavior, providing experimental evidence to support the suggestion that DCN is a potential therapeutic target for FTC.
2025-03-21 | Exploring the tumor suppressor role of RIN1 in familial thyroid carcinoma.
The genetic component is thought to play an important role in the development of familial non-medullary thyroid carcinoma (fNMTC), but the involved molecular mechanisms and genes are poorly understood. The MAPK kinase cascade, particularly involving RAS and BRAF, is crucial in cancer development, with RIN1 emerging as a notable gene due to its differential expression across various tumor types. We identified a frameshift mutation (c.798delC: p.V267Sfs*83) in the RIN1 gene in a family with non-medullary thyroid cancer (NMTC) through whole-exome sequencing. Paraffin-embedded tumor tissues were analyzed to investigate the mutation's characteristics and its potential implications within the thyroid cellular context. Functional assays and RNA sequencing using CRISPR/Cas9-edited Nthy-ori 3-1 thyroid cell line and xenograft zebrafish models confirmed the mutation effect and the putative RIN1 tumor suppressor role. The study revealed significant alterations in cellular behavior upon RIN1 knockout, including increased cell viability, proliferation and colony formation, alongside morphological changes indicative of epithelial-mesenchymal transition. Enhanced phosphorylation of ERK and AKT suggested MAPK pathway dysregulation following RIN1 depletion, supporting its potential tumor suppressive role. Phenotypic rescue experiments confirmed that reintroduction of wild-type RIN1 restored normal cellular behavior. RNA sequencing demonstrated differential gene expression between RIN1-/- and control cells, particularly affecting pathways associated with cancer progression, closely resembled signatures specific to NMTC. This study provides compelling evidence supporting RIN1 as a tumor suppressor gene within thyroid cells. In addition, the findings highlight its potential significance as novel gene involved in FNMTC pathogenesis.
2024-10-23 | Utility of intraoperative Delphian lymph node sampling in pediatric thyroid surgery.
The Delphian lymph node (DLN) is the first lymph node receiving drainage from the thyroid. We aim to determine whether routine DLN sampling with frozen section analysis during pediatric thyroidectomy can alter intraoperative surgical decision making. Additionally, we aim to measure whether DLNs can predict a requirement for central neck dissection (CND) in the clinically node negative (CNN) pediatric population. Retrospective chart review for pediatric patients who underwent thyroidectomy between 2014 and 2022. Patients were included if they had prior FNA with a result of: benign nodule, atypia or follicular neoplasm of undetermined significance (AUS/FNUS), follicular neoplasm (FN), or papillary thyroid carcinoma (PTC). All patients had intraoperative DLN analysis via frozen section histopathology. 27 patients were included, 9 males (33 %) and 18 females (67 %). On final pathology 19 patients (70.4 %) had PTC. The DLN was negative for carcinoma in all (n = 8, 100 %) patients with benign pathology. In 10 patients (100 %) with positive DLN on frozen section, postoperative pathology demonstrated central neck metastasis. Nine (90 %) of these patients were CNN and had alterations in the surgical plan based on the DLN. The tenth patient's surgical plan did not change given preoperative clinical disease. Three patients with negative DLNs had central neck metastasis. The DLN serves a role in guiding treatment for the pediatric population. Positive DLN altered surgical plans in 60 % of CNN PTC patients, allowing for CND to be performed and reducing need for additional surgical resection. The positive predictive value for DLN status was 100 % in this study, and the negative predictive value was 62.5 %. However, negative DLNs do not rule out central neck disease.
small molecules
2026-09-01 | Mechanistic and Clinical Perspectives on Traditional Chinese Medicine in Thyroid Cancer Management.
Thyroid cancer is one of the most prevalent malignancies of the endocrine system, comprising various subtypes such as papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and the aggressive anaplastic thyroid carcinoma (ATC). Despite a generally favorable prognosis for PTC, recurrence, metastasis, and resistance to conventional therapies continue to pose significant challenges. The pathogenesis of thyroid cancer involves genetic mutations in BRAF, RAS, and RET, as well as dysregulated molecular pathways such as MAPK, PI3K/Akt/mTOR, and NF-κB, all of which contribute to cancer progression and therapeutic resistance. This review highlights how Traditional Chinese Medicine (TCM), with its extensive history and a diverse range of bioactive compounds derived from natural sources, offers a complementary approach to thyroid cancer treatment. TCM has been shown to modulate various cellular mechanisms, including inhibiting tumor proliferation, inducing apoptosis, and regulating immune responses. Additionally, TCM can influence the tumor microenvironment (TME), reducing immune evasion and improving therapeutic sensitivity. Many TCM compounds have been identified for their ability to target critical oncogenic signaling pathways, offering a holistic approach to cancer treatment with fewer side effects than traditional chemotherapy. Furthermore, integrating TCM with modern medicine, including novel formulations and nanotechnology, offers the potential to improve efficacy and reduce side effects. The convergence of Artificial Intelligence (AI) and Systems Biology also holds great promise for optimizing personalized treatment regimens and advancing targeted therapies, ultimately improving patient outcomes in thyroid cancer management.
2026-08-27 | ERK Signaling in Thyroid Cancer: Lineage Suppression, Epigenetic Reprogramming, and Theranostic Reversal.
Differentiated thyroid carcinoma is a morphologic diagnosis, not a direct measure of preserved thyroid function. Although most papillary, follicular, and oncocytic thyroid carcinomas retain architectural or cytologic features of follicular-cell derivation, a clinically important subset loses the molecular machinery required for effective iodine transport, organification, and radioiodine therapy. This functional divergence is central to the biology of radioiodine-indifferent and radioiodine-refractory thyroid cancer. This review examines the role of oncogenic MAPK/ERK signaling as a principal regulator of thyroid lineage suppression and therapeutic failure. Aberrant activation of the RAF-MEK-ERK axis, most prominently through BRAF^V600E, RAS alterations, and receptor tyrosine kinase fusions, does more than promote proliferation. It reshapes follicular-cell identity by repressing thyroid-lineage transcriptional programs and silencing iodine-handling genes, including SLC5A5/NIS, TPO, TG, TSHR, SLC26A4, and related components of the iodine metabolic transcriptome. This repression is mediated through coordinated transcriptional, epigenetic, and post-transcriptional mechanisms involving lineage transcription factors such as PAX8, NKX2-1, and FOXE1; chromatin-modifying programs including histone deacetylation and PRC2/EZH2-associated repression; DNA methylation; and non-coding RNA networks. Importantly, ERK-driven functional dedifferentiation is not always a fixed terminal state. Preclinical models and early clinical trials demonstrate that pharmacologic inhibition of the MAPK pathway can restore iodine avidity in selected radioiodine-refractory tumors, creating the theranostic basis for redifferentiation therapy. Iodine-124 PET/CT and lesion-level dosimetry have shown that restored iodine uptake can be measured diagnostically and then exploited therapeutically with iodine-131. However, clinical translation remains limited by inter- and intratumoral heterogeneity, incomplete durability of response, adaptive pathway reactivation, persistent epigenetic repression, tumor microenvironmental influences, and the absence of standardized dosimetric thresholds. We propose that advanced follicular-cell-derived thyroid cancers should be understood along a functional differentiation continuum rather than through morphology alone. Within this framework, radioiodine refractoriness reflects not merely treatment failure, but a therapeutically interrogable state of lineage suppression. Refinement of redifferentiation therapy will require genotype-informed patient selection, functional imaging, standardized dosimetry, rational combination strategies, and prospective trials capable of distinguishing true restoration of radioiodine therapeutic efficacy from the antiproliferative effects of kinase inhibition alone.
2026-07-23 | Autophagy in thyroid cancer: stage-dependent switch, mutation-specific regulation, and therapeutic targeting.
Autophagy plays context-dependent roles in thyroid cancer, but whether its dual nature represents a reversible balance or an irreversible stage-dependent switch has remained unclear. This review synthesizes evidence across papillary, follicular, medullary, and anaplastic thyroid carcinoma subtypes and reveals that the transition from tumor-suppressive to tumor-promoting autophagy is unidirectional and driven by disease progression, not a simultaneous equilibrium. The major driver mutations BRAF V600E, RAS, and RET regulate autophagy through distinct mechanisms, demanding subtype-specific therapeutic strategies rather than a uniform approach. Importantly, autophagy is an adaptive resistance mechanism rather than a primary driver, as no thyroid cancer is driven by mutations in autophagy genes. Consequently, autophagy inhibitors will not work as monotherapy but may sensitize tumors to standard treatments that create therapeutic stress. Current clinical translation remains stalled by poor inhibitor specificity, lack of validated biomarkers, and unknown treatment timing. We conclude that the field should move from descriptive studies to biomarker-enriched, hypothesis-driven trials, prioritizing anaplastic thyroid carcinoma for hydroxychloroquine-TKI combinations while standardizing assays for p62 and LC3B to enable patient selection.
2026-06-22 | Multidisciplinary treatment of follicular thyroid carcinoma with hepatic and pulmonary metastases: a case report and literature review.
To determine the clinical diagnostic features, molecular basis, and comprehensive treatment strategies for a case of follicular thyroid carcinoma (FTC) with hepatic and pulmonary metastases that developed 8 years after surgery for a Follicular Tumor of Uncertain Malignant Potential (FT-UMP), and to provide a basis for long-term follow-up and individualized treatment of such borderline tumors. FTC is the second most common subtype of differentiated thyroid cancer. Currently, the diagnosis and management of distant FTC metastases remain a critical challenge, particularly when they occur in rare locations, such as the liver. This article reports the case of a 56-year-old male patient. Within 8 years after the resection of the well-differentiated follicular neoplasm of FT-UMP, a single mass in the lateral lobe of the left liver and multiple nodules in both lungs were detected in the patient. Following a multidisciplinary team (MDT) discussion, the decision was made to perform a robot-assisted hepatectomy. Pathology confirmed the diagnosis of FTC metastasis. Subsequently, we formulated a comprehensive treatment plan including total thyroidectomy, radioactive iodine (RAI) therapy with 131I and endocrine treatment. Active surveillance was adopted for the lung metastases. Twelve months of follow-up showed no signs of recurrence. This case highlights that for patients with FT-UMP, continuous monitoring is also crucial for the early detection of metastasis. In complicated cases with liver and lung metastases from FTC, MDT collaboration is essential to formulate individualized treatment plans integrating multidisciplinary expertise and multimodal therapies.
2026-06-08 | Pathology-based thermal ablation safety margin for follicular adenoma: a digital whole-slide study of follicular carcinoma invasion.
Follicular adenoma (FA) and follicular thyroid carcinoma (FC) are difficult to differentiate before surgery, raising concerns that thermal ablation (TA) of FA might treat an occult minimally invasive FC. Therefore, the microscopic extent of FC invasion was quantified to propose a pathology-informed ablation safety margin. A retrospective analysis was conducted on 43 surgically resected FCs treated between 2016 and 2023. Two readers independently reviewed the pathological images (×40 magnification). The capsule infiltration distance (the maximum depth of infiltration beyond the capsule) and the minimally invasive infiltration distance (the ultrasound-undetectable occult infiltration depth) were measured. These distances were compared by tumor stage, FC pathological classification, and lymph node metastasis (LNM). The capsule infiltration distance ranged from 0.14 to 6.10 mm (mean, 1.49 ± 1.22). The minimally invasive infiltration distance ranged from 0.09 to 1.36 mm (mean, 0.56 ± 0.37). The distances did not differ by tumor stage, FC pathological classification, sex, or lymph node metastasis (LNM) (all P > 0.05). Age was associated with a larger capsule infiltration distance (P = 0.040). However, age was not associated with the minimally invasive infiltration distance (P = 0.367). The minimally invasive infiltration in FC did not exceed 1.36mm in this cohort. Since the actual ablation area achieved by clinical TA exceeds the pathological margin, this supports the extended ablation safety margin of 2mm beyond the sonographic tumor boundary. This TA margin could cover occult minimally invasive FC.
proteins
2025-09-04 | Identification of BCL2L11 as a Candidate Gene for Hereditary Predisposition to Non-Medullary Thyroid Cancer Using Familial Whole-Exome-Sequencing.
Familial non-medullary thyroid cancer, defined as two or more affected first-degree relatives, accounts for 3%-9% of thyroid cancers. It is associated with more aggressive cancer, early age at diagnosis, multifocality, and increased risk of metastasis and recurrence. Although no high penetrance predisposing gene has been identified at present, the estimated contribution of genetics is significant. Our study explored five families presenting FNMTC using Whole-Exome Sequencing and found three candidate genes: TELO2 in one family, UACA and BCL2L11 in another. All of these tumor suppressor genes are expressed in the thyroid, exhibit under-expression in tumor tissue compared to healthy tissue both in silico and in our samples, and two of them are known to be involved in thyroid carcinogenesis via the FOXO3A pathway. Functional analysis to validate these candidate genes in thyroid cancer cells showed that one of the three, BCL2L11, has a tumor suppressor effect on proliferation and apoptosis. Their impact on hereditary predisposition to thyroid cancer, as well as their combined effects, requires further study. Indeed, a case-control study would be essential to determine the diagnostic utility of their routine analysis.
2025-07-17 | ANTP-SmacN7 enhances radiosensitivity in TPC-1 cells through XIAP-mediated activation of apoptotic protein.
A subset of differentiated thyroid cancer still lacks effective treatment options, such as locally advanced or metastatic patients. Some of these patients also need to try radiation therapy. The objective of this study is to investigate the potential of the antennapedia-modified SMAC fragment (ANTP-SmacN7) as a radiation sensitizer to enhance the therapeutic efficacy of radiotherapy in papillary carcinoma of thyroid (PTC), ascertain the contribution of X-linked inhibitor of apoptosis protein (XIAP), and explore its associated mechanisms to the apoptotic response in PTC. Methods To determine whether ANTP-SmacN7 enhances radiotherapy sensitivity by promoting apoptosis through XIAP in thyroid cancer, we first performed bioinformatics analysis of XIAP in thyroid cancer (THCA) using TCGA/GTEx THCA datasets. This analysis evaluated XIAP expression levels, its correlation with clinical pathological features and prognosis, functional enrichment, and interactions with apoptosis-related genes of CASP. Subsequently, we treated TPC-1 cells with gamma ray and ANTP-SmacN7 in different groups and assessed cell proliferation, migration, and apoptosis-related protein expression (XIAP, caspase-3, caspase-8, and caspase-9) using CCK-8, colony formation, transwell assays, annexin V/PI double staining, and western blotting. To further elucidate the role of XIAP and the effects of ANTP-SmacN7, we constructed XIAP-overexpressing TPC-1 cells, treated them with gamma ray and ANTP-SmacN7 in different groups, and compared changes of cell function and apoptosis-related protein. XIAP is highly expressed in THCA and demonstrates significant correlations with aggressive clinicopathological features including advanced T stage (p = 0.018) and extrathyroidal extension (p = 0.017) in THCA, while its prognostic stratification potential is evidenced by an AUC of 0.63. It interacts closely with CASP family members involved in apoptosis, which might critically inform therapeutic strategies for radioresistant THCA. The experimental results demonstrate that TPC-1 cells are sensitive to low-dose gamma ray but exhibit radioresistant as the radiation dose increases. While ANTP-SmacN7 significantly enhances gamma ray-induced radiosensitization. When combined with gamma ray, ANTP-SmacN7 markedly reduces cell proliferation, viability, and migration, while simultaneously promoting apoptosis. This effect is mediated by XIAP inhibition, which activates the intrinsic apoptosis pathway through caspase-3 and caspase-9. Additionally, XIAP influences the extrinsic apoptosis pathway by directly or indirectly upregulating caspase-8. ANTP-SmacN7 could be a probable candidate for a pharmaceutical radiosensitizer when combined with gamma ray for the treatment of PTC. These findings may provide a theoretical basis for the development of radiosensitization strategies for locally advanced or metastatic patients.
2025-03-17 | Identification of GPX3 and JUN as Tumor Suppressors in Thyroid Cancer through Integrated WGCNA and Mendelian Randomization.
Background: Thyroid cancer (TC) ranks among the most common malignancies globally, with an increasing incidence among younger populations. While papillary thyroid carcinoma (PTC) generally has a favorable prognosis, other forms of TC, such as anaplastic thyroid carcinoma (ATC), are associated with poor outcomes. Although specific mutations, such as BRAFV600E, have been identified in certain types of TC, the underlying mechanisms remain largely unclear. Therefore, there is a critical need to further explore therapeutic targets associated with malignant tumors to improve treatment outcomes. Method: We integrated eQTL data from European populations with RNA-Seq data from TC patients obtained from TCGA and multiple GEO databases. Through differential expression analysis, WGCNA, and Mendelian randomization (MR) analysis, we sought to identify potential gene therapy targets in TC. Additionally, we explored the biological behaviors of these targets using various cellular biology assays, such as MTT, colony formation, wound healing, and Transwell assays. Molecular biology techniques, including Western blot, were employed to investigate the underlying mechanisms. Result: Differential expression analysis across six GEO datasets identified 649 genes associated with TC. Subsequent WGCNA analysis of the GSE6339 dataset revealed 2,739 genes, and MR analysis further identified 189 genes. The intersection of these datasets highlighted four key genes: TIAM1, RAP1GAP, GPX3, and JUN. GO analysis linked these genes to "response to oxidative stress" and "regulation of GTPase activity". KEGG pathway analysis demonstrated significant enrichment in pathways including "Glutathione metabolism", "cAMP signaling pathway", "Rap1 signaling pathway", "Tight junction", and "Thyroid hormone synthesis". Further, single-gene GSEA analyses suggested distinct pathways through which each gene may influence TC progression. Immune profiling revealed marked differences in immune cell populations, notably CD8+ T cells, monocytic lineage cells, neutrophils, NK cells, and T cells, between normal and cancerous thyroid tissues. Notably, RAP1GAP, GPX3, and JUN were implicated in the regulation of Treg and follicular helper T cell functions. The differential expression of these genes was rigorously validated using TCGA dataset and six additional GEO datasets. While the tumor-suppressive roles of TIAM1 and RAP1GAP have been previously established, our findings reveal that the overexpression of GPX3 and JUN significantly impairs the proliferative and migratory capacities of TC cells, underscoring their potential as therapeutic targets. Conclusion: This study identifies GPX3 and JUN as critical tumor suppressor genes in TC, with their function closely linked to T regulatory cells and follicular helper T cells. The overexpression of GPX3 and JUN demonstrates significant tumor-suppressive activity, highlighting their potential as effective therapeutic targets in combating TC.
2024-01-18 | YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling.
N6-Methyladenosine (m6A) mRNA methylation modification is regarded as an important mechanism involved in diverse physiological processes. YT521-B homology (YTH) domain family members are associated with the tumorigenesis of several cancers. However, the role of YTHDC2 in papillary thyroid cancer (PTC) progression remains unknown. Results showed that YTHDC1, YTHDF1, YTHDF2, and YTHDF3 showed no observable difference in thyroid cancer samples. YTHDC2 was significantly downregulated in thyroid cancer samples and cells. YTHDC2 inhibited cell proliferation in PTC cells. YTHDC2 elicited apoptosis in PTC cells, as demonstrated by the elevated expression of pro-apoptotic factors cl-caspase-3/caspase-3 and Bcl-2-associated (Bax), and the reduced anti-apoptotic B cell lymphoma-2 (Bcl-2) expression. There was a positive correlation between YTHDC2 and cylindromatosis (CYLD) expression based on GEPIA database. YTHDC2 increased CYLD expression in PTC cells. CYLD knockdown abolished the effects of YTHDC2 on PTC cell proliferation and apoptosis. Additionally, YTHDC2 inactivated the protein kinase B (Akt) pathway by increasing CYLD in PTC cells. Overall, YTHDC2 inhibited cell proliferation and induced apoptosis in PTC cells by regulating CYLD-mediated inactivation of Akt pathway.
2022-07-28 | USP13 genetics and expression in a family with thyroid cancer.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and its incidence has greatly increased in the last 30 years. Ubiquitin-specific protease 13 (USP13) is a class of deubiquitinating enzymes (DUBs) and plays an important role in cellular functions such as cell cycle regulation, DNA damage repair, and different cell signaling pathways. Studies regarding the role of USP13 in cancer development and progression are divergent and there are no previous data regarding the role of USP13 gene in PTCs. In this study, we investigated the genetic cause of PTC diagnosed in multiple members of a Brazilian family. Whole exome sequencing (WES) was performed to identify the genetic cause of PTC. Cycloheximide chase assay and clonogenic assay were performed to study USP13 stability and function in vitro. WES analysis identified a heterozygous missense variant c.1483G > A (p.V495M) in the USP13 gene that fully segregates with the disease. In silico modeling suggests that this variant may cause protein structural perturbations. USP13 overexpression increased the potential of a single cell to form colonies. The USP13 c.1483G > A variant enhanced the effects seen in USP13 overexpression and preserved protein stability for longer hours compared to the non-mutated USP13 protein. Our study suggests that USP13 overexpression may play a role in tumorigenesis of PTCs; and that the USP13 p.V495M (c.1483G > A) variant enhances USP13 estability.
antibodies
2026-03-02 | Advances in immunotherapy for thyroid malignancies: from molecular targets to clinical outcomes.
Thyroid cancers comprise a diverse collection of endocrine tumors, notably papillary, follicular, medullary, and anaplastic carcinomas, each differentiated by their molecular alterations, clinical behavior, and responsiveness to therapies. Current treatment algorithms of surgical resection, radioiodine treatment, and selective small-molecule inhibitors, although effective for many cases, confront significant limitations, particularly in anaplastic and advanced medullary tumors, where resistance to conventional agents correlates with diminished prognosis, thereby demanding the exploration of innovative therapeutic strategies. This article reviews contemporary immunotherapy-directed interventions for thyroid cancers, highlighting the elucidation of actionable tumor antigens, the reengineering of the immunologic tumor microenvironment, and the ongoing efforts to translate these laboratory findings into practicable, evidence-based clinical protocols. Recent studies underscore the critical efficacy of immune checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 pathways in select populations of anaplastic thyroid carcinoma (ATC), medullary thyroid carcinoma (MTC), and PD-L1-expressing differentiated thyroid cancers. Next-generation immune modulators, specifically inhibitors directed against LAG-3 and TIM-3, are being evaluated in combinatorial frameworks. Vaccines engineered to elicit responses against the BRAF V600E mutation, RET/PTC fusions, and additional neoantigens have shown promising immunogenic profiles in preliminary trial cohorts, while adoptive transfer methodologies, including tumor-infiltrating lymphocyte (TIL) mobilization and engineered CAR-T lymphocytes, are progressing through preclinical and early-phase clinical benchmarks. Concurrently, oncolytic viral vectors are being harnessed to amplify neoantigen liberation and, consequently, to amplify systemic immunity. When immunotherapeutic modalities are judiciously aligned with tyrosine kinase inhibitors (TKIs) or radiotherapeutic regimens, cumulative anti-tumor effects are accentuated, purportedly through mechanisms such as immunogenic cell death induction and the reprograming of immune-tolerant tumor ecosystems. Immunotherapy is set to transform the treatment paradigm for thyroid cancers, although remaining hurdles, the disquietingly low baseline immunogenicity of differentiated tumors, the rapid, capricious emergence of resistance, and complex immune-related endocrine toxicities, must be systematically addressed. Success in this arena will hinge on utilitarian biomarker-based cohort selection, the discovery of fresh immunogenic epitopes, and the meticulous design of synergistic treatment combinations. The synergistic leverage of genomic, transcriptomic, and immune landscape dissection, coupled with cutting-edge engineered lymphocyte platforms and engineered oncolytic vectors, may finally position immunotherapy as an unassailable pillar of bespoke medicine for advanced thyroid carcinomas.
2026-02-22 | Milk fat globule-EGF factor 8 enhances the proliferation and migration of thyroid carcinoma cells through epithelial-mesenchymal transition and PI3K/AKT signaling pathway.
Milk fat globule-EGF factor 8 (MFG-E8) has been found to be involved in the development and progression of several carcinomas. However, the role of MFG-E8 in thyroid carcinoma has not been studied yet. This study aimed to investigate the expression and function of MFG-E8 in thyroid carcinoma (TC). Single-cell RNA sequencing, transcriptome sequencing, mass spectrometry, and immunohistochemistry were used to analyze MFG-E8 expression in papillary thyroid carcinoma (PTC). Western blotting and RT-PCR were performed to assess MFG-E8 expression in TC cell lines. Stable MFG-E8 knockdown cell lines were established, and functional assays were conducted to evaluate the effects of MFG-E8 on TC cell proliferation, migration, and invasion. Bioinformatics analysis and Western blotting were employed to explore the potential downstream signaling pathways. The association between MFG-E8 expression and immune cell infiltration in the tumor microenvironment was also analyzed using bioinformatics tools. MFG-E8 expression was significantly upregulated in PTC tumor tissues. It was closely associated with specific PTC subtypes, with higher expression observed in the tall-cell subtype compared to the classic and follicular subtypes. Knockdown of MFG-E8 significantly inhibited TC cell proliferation, migration, and invasion. Mechanistically, MFG-E8 was found to be associated with the regulation of epithelial-mesenchymal transition (EMT)-related processes and linked to the modulation of the PI3K/AKT signaling pathway in TC cells. Furthermore, MFG-E8 correlated with the formation of an immunosuppressive tumor microenvironment by modulating immune cell infiltration and activating the PI3K/AKT pathway in immune cells. Our findings identify MFG-E8 as a key driver of thyroid carcinoma progression, particularly in aggressive subtypes, and highlight its translational value as a prognostic biomarker and promising therapeutic target by targeting the MFG-E8-PI3K/AKT-EMT axis-providing a new clinical framework for personalized treatment of TC.
2026-02-02 | CXCL8/SDC1 axis mediates tumor stem cell interactions to drive remote transfer in thyroid cancer.
This study explores the molecular mechanisms behind the remote transfer of thyroid cancer (THCA) by investigating the interaction network of C-X-C motif chemokine ligand 8+ (CXCL8+ monocytes and syndecan-1+ (SDC1+) tumor stem cells using single-cell and spatial transcriptome sequencing. Tumor samples from THCA patients were analyzed using single-cell RNA sequencing (scRNA-seq), spatial transcriptome sequencing, and tumor tissue transcriptome analysis. Data were processed with Seurat and CellChat R packages, integrated via the SPOTlight package, and correlated with clinical data from the UCSC Xena database. Functional pathway enrichment analyses were performed using Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genome (KEGG). In vitro, a co-culture system of monocytes and THCA stem cells was developed, and protein levels were measured via enzyme-linked immunosorbent assay (ELISA) and Western blotting. The self-renewal and migration of follicular thyroid carcinoma (FTC) 238-S cells were assessed through sphere formation, colony formation, Cell Counting Kit-8 (CCK-8), and Transwell assays. In vivo, a subcutaneous tumor xenograft model and a lung metastasis model were established in nude mice. Transcriptomic analyses identified the CXCL8/SDC1 axis as a key mediator of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling activation, promoting THCA stem cell self-renewal, invasion, and metastasis. CXCL8/SDC1 expression was significantly higher in the high-risk C1 subtype of THCA patients and correlated with a worse prognosis. In vitro and animal studies confirmed that the CXCL8/SDC1 axis drives tumor progression and metastasis. The interaction between CXCL8+ monocytes and SDC1+ tumor stem cells activates the JAK-STAT pathway, facilitating the remote transfer of THCA. Targeting the CXCL8/SDC1 axis may provide novel therapeutic strategies for improving THCA patient outcomes.
2025-09-22 | Multi-omics analysis and metastasis risk factor prediction in N1b stage PTMC: insights into immune infiltration and therapeutic implications.
Papillary thyroid microcarcinoma (PTMC) with lateral neck lymph node involvement exhibits a deceptively indolent yet highly invasive phenotype, characterized by early dissemination and slow tumor growth. A comprehensive understanding of integrating multiomics landscapes, circulating immune profiles, and tumor immune microenvironment is essential for more accurate surveillance and tailored therapeutic strategies. Clinical profile and circulating immune-inflammatory markers from 638 PTMC patients were analyzed using multivariate and least absolute shrinkage and selection operator (LASSO) regression to recognize N1b-associated risk indicators. Eight supervised machine learning models were trained via 10-fold cross-validation to select the optimal classifier. Weighted gene coexpression network analysis (WGCNA) alongside machine learning identified metastasis-related gene modules from the integrated RNA-seq profile, leading to a multilayer perceptron gene classifier. Genomic profiling was employed to investigate mutations, copy number alterations, and methylation modifications in signature genes, followed by screening of antineoplastic drugs and docking simulations to explore their therapeutic potential. CIBERSORT, combined with immunohistochemistry, was used to investigate immune infiltration and functional changes in N1b-stage PTMC lesions. Two clinical metastasis risk models were developed, with Model A based on the neutrophil-to-lymphocyte ratio (NLR) and Model B on lymphocyte and neutrophil counts, where Model A showed superior generalization (AUC = 0.852) and discriminative performance. NLR was an independent risk determinant for N1b-stage PTMC (OR = 2.12, p < 0.01). Transcriptomic profiling revealed a molecular signature (ALDH1A3, CTXN1, MGAT3, and TMEM163) of occult lateral lymph node metastasis, exhibiting strong robustness (AUC = 0.857). Signature genes were predominantly associated with cell adhesion, intercellular signaling, and KRAS dysregulation pathways. Hypomethylation of CTXN1, MGAT3, and TMEM163 may underlie transcriptional activation. N1b-stage tumors exhibited reduced CD8+ T and T follicular helper cell infiltration but increased dendritic, γδ T, and activated CD4+ memory T cells, suggesting immune evasion and compensatory immune activation. This study constructed a robust metastasis prediction nomogram for N1b-stage PTMC and identified metastasis-associated molecular drivers through integrative multiomics analysis. Comprehensive profiling of systemic and tumor-infiltrating immunity revealed key antitumor immune alterations. These findings establish a framework for early metastatic phenotype detection, potentially inspiring relevant immunotherapeutic hypotheses.
2025-05-21 | Proteomic analysis reveals modulation of key proteins in follicular thyroid cancer progression.
Cytopathology cannot be used to reliably distinguish follicular thyroid adenoma (FTA) from follicular thyroid carcinoma (FTC), the second most common form of thyroid cancer, because they exhibit nearly identical cellular morphology. Given the challenges in diagnosis and treatment, this study aims to identify the mechanisms underlying FTC is essential. Using parallel reaction monitoring-mass spectrometry (PRM-MS) assays, we identified and quantified 94 differentially expressed protein candidates from a retrospective cohort of 1085 FTC and FTA tissue samples from 18 clinical centers. Of these targeted proteins, those with the potential for distinguishing FTC from FTA were prioritized using machine learning. Co-immunoprecipitation (co-IP) and immunofluorescence co-localization assays, as well as gene interference, overexpression, and immunohistochemistry (IHC) experiments, were used to investigate the interactions and cellular functions of selected proteins. Using machine learning models and feature selection methods, 30 of the 94 candidates were prioritized as key proteins. Co-IP and immunofluorescence co-localization assays using FTC cell lines revealed interactions among insulin-like growth factor 2 receptor (IGF2R), major vault protei (MVP), histone deacetylase 1 (HDAC1), and histone H1.5 (H1-5). Gene interference and overexpression experiments in FTC-133 cells confirmed the promotional role of these proteins in cell proliferation. IHC assays of patient samples further confirmed elevated expression of these four proteins in FTC compared with that in FTA. Our findings underscore the utility of advanced proteomic techniques in elucidating the molecular underpinnings of FTC, highlighting the potential significance of IGF2R, MVP, HDAC1, and H1-5 in FTC progression, and providing a foundation for the exploration of targeted therapies.
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2026-09-16 | Clinical Relevance and Regulatory Mechanisms of LINC01521 in Papillary Thyroid Carcinoma.
Papillary thyroid carcinoma (PTC) is a well-differentiated malignancy derived from thyroid follicular epithelial cells. This study explores the functional role and underlying mechanisms of LINC01521 in PTC, aiming to provide new strategies to improve prognostic assessment and survival rates for PTC. The study cohort comprised 120 patients with PTC. LINC01521 expression in PTC tissues and cells was quantified by qRT-PCR. The association between LINC01521 and PTC malignant progression and adverse prognosis was evaluated by the chi-square test. The target relationship between LINC01521 and miR-4319 was confirmed by the starBase database. The effects of LINC01521 on PTC cell behavior and cuproptosis were examined by CCK8, Transwell, and related kits, and the potential regulatory mechanisms involved were further elucidated. LINC01521 was markedly upregulated in PTC tissues and cells. High LINC01521 expression is closely linked to the malignant clinical features of PTC, including more tumor lesions, increased tumor size, more advanced TNM staging, higher LNM rates, and poorer tumor differentiation. LINC01521 is an independent prognostic risk factor for PTC. Elevated LINC01521 levels indicated shorter overall survival. LINC01521 targets and regulates miR-4319. LINC01521 knockdown led to a significant decrease in the proliferation, migration, and invasion of PTC cells. LINC01521 overexpression attenuated ES + Cu2+ induced cuproptosis, while miR-4319 overexpression reversed these effects. LINC01521 acts as a promising prognostic marker for predicting PTC malignant progression and adverse outcomes. LINC01521 promotes PTC progression by affecting PTC cell function and inhibiting cuproptosis, and the possible regulatory mechanism is through targeting miR-4319.
2024-11-04 | Clinically aggressive follicular cell-derived thyroid carcinoma: A comprehensive series with histomolecular characterization and discovery of novel gene fusions.
Thyroid cancer rates are increasing, mostly with a good prognosis and less than 2 % of cases are more aggressive. Recent efforts focus on understanding molecular events predicting tumor aggressiveness and treatment targets in advanced thyroid cancer. This study concerned 57 patients with aggressive metastatic, and/or radioiodine-refractory thyroid carcinomas, excluding anaplastic cases. Molecular profiling, including next-generation sequencing and RNA sequencing, was conducted to dissect the complex molecular landscape of these aggressive tumors. Histopathological analysis indicated that papillary carcinomas and high-grade thyroid carcinomas were predominant. The molecular analysis revealed a spectrum of mutations, with prevalent occurrences of BRAF V600E, TERT promoter, and RAS mutations. RNA sequencing identified ten gene fusions, such as NTRK and RET fusions. Three novel fusions were discovered: UGGT1::TERT, BTBD9::TERT, and TG::IGF1R, potentially driving aggressive behavior. UGGT1::TERT was linked to radioiodine-refractory tall cell PTC, BTBD9::TERT to high-grade follicular PTC, and TG::IGF1R to oncocytic carcinoma. These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.
2024-07-24 | Oncogenic pseudogene DUXAP10 knockdown suppresses proliferation and invasion and induces apoptosis of papillary thyroid carcinoma cells by inhibition of Akt/mTOR pathway.
Pseudogenes, another novel group of non-coding segments without protein-coding capacity, are closely associated with tumourigenesis and cancer progression. Double homeoboxA pseudogene 10 (DUXAP10) is reported to be robustly expressed in thyroid carcinoma. However, the functional role and underlying mechanism of DUXAP10 in papillary thyroid carcinoma (PTC) progression remain undefined. DUXAP10 expression in PTC cells was detected by qRT-PCR. Cell proliferation and invasion were determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell invasion assay, respectively. Apoptosis was evaluated using flow cytometry. Protein expression of matrix metalloproteinase (MMP)-2, MMP-9, protein kinase B (Akt), phosphorylated Akt, mammalian target of rapamycin (mTOR), and phosphorylated mTOR was examined by western blot. Results showed that DUXAP10 was significantly overexpressed in PTC cells compared with normal thyroid follicular epithelium cells. DUXAP10 silencing suppressed cell proliferation and invasive ability, reduced the expression of MMP-2 and MMP-9, and increased apoptotic rate and caspase-3 activity in PTC cells. Additionally, the Akt/mTOR pathway was inhibited following DUXAP10 knockdown in PTC cells. Activation of the Akt/mTOR pathway by 740Y-P and MHY1485 attenuated DUXAP10 knockdown-induced proliferation reduction, invasion suppression and apoptosis in PTC cells. In conclusion, DUXAP10 knockdown suppressed proliferation and invasion and induced apoptosis in PTC cells at least partially by inhibition of the Akt/mTOR pathway.
2024-03-08 | Translocated HMGB3 is involved in papillary thyroid cancer progression by activating cytoplasmic TLR3 and transmembrane TREM1.
The family of high mobility group box (HMGB) proteins participates in various biological processes including immunity, inflammation, as well as cancer formation and progression. However, its role in thyroid cancer remains to be clarified. We performed quantitative RT-PCR (qRT-PCR), western blot, enzyme-linked immunosorbent, immunohistochemistry, and immunofluorescence assays to evaluate the expression level and subcellular location of HMGB3. The effects of HMGB3 knockdown on malignant biological behaviors of thyroid cancer were determined by cell proliferation assays, cell cycle and apoptosis assays, and transwell chamber migration and invasion assays. Differential expression genes (DEGs) altered by HMGB3 were analyzed using the Ingenuity Pathway Analysis (IPA) and TRRUST v2 database. HMGB3 correlated pathways predicted by bioinformatic analysis were then confirmed using western blot, co-immunoprecipitation, dual-luciferase reporter assay, and flow cytometry. We found that HMGB3 is overexpressed and its downregulation inhibits cell viability, promotes cell apoptosis and cell cycle arrest, and suppresses cell migration and invasion in thyroid cancer. In PTC, both tissue and serum levels of HMGB3 are elevated and are correlated with lymph node metastasis and advanced tumor stage. Mechanistically, we observed the translocation of HMGB3 in PTC, induced at least partially by hypoxia. Cytoplasmic HMGB3 activates nucleic-acid-mediated TLR3/NF-κB signaling and extracellular HMGB3 interacts with the transmembrane TREM1 receptor in PTC. This study demonstrates the oncogenic role of HMGB3 cytoplasmic and extracellular translocation in papillary thyroid cancers; we recommend its future use as a potential circulating biomarker and therapeutic target for PTC.
2024-03-04 | Spatial transcriptomics reveals prognosis-associated cellular heterogeneity in the papillary thyroid carcinoma microenvironment.
Papillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study. In conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis. The spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment. The occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.
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2026-06-19 | MCM2 germline variants predispose to familial papillary thyroid carcinoma due to genomic instability caused by MCM complex disruption.
In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a hereditary subtype for which large-scale clinical cohort studies are lacking and definitive susceptibility genes remain elusive. A large fPTC clinical cohort (171 cases), 490 sporadic papillary thyroid carcinoma (sPTC) patients, and 500 healthy blood samples from physical examination were collected in the study. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were used to screen for susceptibility genes. Three MCM2 gene mutations (c.1092 C > G, p.N364K; c.1975A>G, p.I659V; and c. 2379 G > A, p.M793I) in 8 patients from 4 distinct families were identified as candidate susceptibility variants. These mutations disrupt the interaction of MCM2 with its partner proteins (MCM3-7), leading to ubiquitination of free MCM monomers. Levels of DNA damage, γ-H2AX foci, RPA foci, and micronucleus formation were significantly elevated in MCM2-deficient cells. Cell-derived xenograft (CDX) modeling, combined with WES and RNA-seq analyses, revealed that MCM2-deficient tumors exhibited significantly faster growth rates and increased chromosomal instability (CIN). MAPK signaling and the PI3K-AKT pathway were significantly over-activated in MCM2-deficient tumors. In our study, based on the fPTC cohort, germline variants of MCM2 predispose to fPTC. The variants disrupt the MCM complex, leading to ubiquitination of free monomeric MCM proteins. MCM2 deficiency induces cell cycle arrest, DNA damage, and CIN, ultimately accelerating tumorigenesis through oncogenic pathway activation. These findings identify MCM2 as a low-frequency, moderately penetrant susceptibility gene for fPTC and underscore the clinical value of MCM2 testing in informing early detection, preventive management, and precision treatment strategies for familial papillary thyroid carcinoma.
2025-11-23 | Tumor-infiltrating T Lymphocytes Recognize Thyroid-specific Proteins and Neo-antigens in Follicular Cell-derived Thyroid Cancers.
Thyroid cancers are among the growing list of cancer types that are resistant to immune-checkpoint inhibitor monotherapy. Although T-cell infiltration is common in follicular cell-derived thyroid cancers, tumor mutation burden is low. The antigenic potential of thyroid cancers is unknown. To investigate the anti-tumor T-cell response in thyroid cancer, we expanded tumor-infiltrating lymphocytes (TIL) from primary thyroid tumors and tumor-involved lymph nodes (TILN). Putative neoantigens and both tissue-associated and tumor-associated antigens were identified by targeted sequencing and RNA-seq. HLA typing was performed for all patients, and neoantigen binding potential was predicted for each patient using NetMHCpan 4.1 and NetMHCIIpan 4.0 algorithms. In parallel, T-cell receptor β sequencing was performed to detect T-cell clonal expansions in patient-matched primary tumors and TILN. TIL reactivity to tumor-associated antigens and neoantigens was determined in vitro by interferon γ ELISA and flow cytometry. Tumor-infiltrating T cells were evident in all thyroid tumors and readily expanded ex vivo. Shared clones were present in primary thyroid tumors and matched TILN in all patients tested, constituting 1% to 10% of the sequenced clones in 6/8 patients. T-cell reactivity to thyroid tissue-specific proteins, thyroid peroxidase and thyroglobulin, was observed in 84.6% (11/13) and 69.2% (9/13) patients, respectively. A BrafV600E-specific T-cell response was evident in 80% (4/5) BrafV600E+ patients. T cells reactive to gene fusion-derived neoantigens were detected in patients with TPR-NTRK1+ and CCDC6-RET+ thyroid cancer. Our studies confirm the presence of tumor antigen-specific T cells in patients with thyroid cancer and encourage further exploration of T cell-targeted immunotherapies for patients with progressive, treatment refractory thyroid cancer.
2025-06-12 | Overexpression of decorin gene influences the biological behaviors of follicular thyroid carcinoma cells.
The objective of the present study was to examine the impact of decorin (DCN) gene overexpression on the proliferation, migration and invasion of human follicular thyroid carcinoma (FTC) cells. DCN expression was evaluated by western blotting (WB) in Nthy-ori3-1 normal thyroid cells and in two FTC cell lines, namely FTC-133 and FTC-238. Lentiviral transfection was employed to overexpress DCN in the FTC cells, with the overexpression efficiency confirmed through reverse transcription-quantitative polymerase chain reaction and WB. Cell viability, colony formation, wound healing and Transwell invasion assays were conducted to assess the proliferation, migration and invasion of the transfected cells. The results revealed that DCN expression in FTC-133 and FTC-238 cells was significantly lower compared with that in Nthy-ori3-1 cells. Successful lentiviral overexpression of DCN in the FTC cell lines significantly decreased the proliferation and colony formation abilities of the cells, and diminished their wound healing and invasive capabilities. This indicated that the lentivirus-mediated overexpression of DCN in FTC-133 and FTC-238 cells altered their cellular behavior, providing experimental evidence to support the suggestion that DCN is a potential therapeutic target for FTC.
2025-03-21 | Exploring the tumor suppressor role of RIN1 in familial thyroid carcinoma.
The genetic component is thought to play an important role in the development of familial non-medullary thyroid carcinoma (fNMTC), but the involved molecular mechanisms and genes are poorly understood. The MAPK kinase cascade, particularly involving RAS and BRAF, is crucial in cancer development, with RIN1 emerging as a notable gene due to its differential expression across various tumor types. We identified a frameshift mutation (c.798delC: p.V267Sfs*83) in the RIN1 gene in a family with non-medullary thyroid cancer (NMTC) through whole-exome sequencing. Paraffin-embedded tumor tissues were analyzed to investigate the mutation's characteristics and its potential implications within the thyroid cellular context. Functional assays and RNA sequencing using CRISPR/Cas9-edited Nthy-ori 3-1 thyroid cell line and xenograft zebrafish models confirmed the mutation effect and the putative RIN1 tumor suppressor role. The study revealed significant alterations in cellular behavior upon RIN1 knockout, including increased cell viability, proliferation and colony formation, alongside morphological changes indicative of epithelial-mesenchymal transition. Enhanced phosphorylation of ERK and AKT suggested MAPK pathway dysregulation following RIN1 depletion, supporting its potential tumor suppressive role. Phenotypic rescue experiments confirmed that reintroduction of wild-type RIN1 restored normal cellular behavior. RNA sequencing demonstrated differential gene expression between RIN1-/- and control cells, particularly affecting pathways associated with cancer progression, closely resembled signatures specific to NMTC. This study provides compelling evidence supporting RIN1 as a tumor suppressor gene within thyroid cells. In addition, the findings highlight its potential significance as novel gene involved in FNMTC pathogenesis.
2024-10-23 | Utility of intraoperative Delphian lymph node sampling in pediatric thyroid surgery.
The Delphian lymph node (DLN) is the first lymph node receiving drainage from the thyroid. We aim to determine whether routine DLN sampling with frozen section analysis during pediatric thyroidectomy can alter intraoperative surgical decision making. Additionally, we aim to measure whether DLNs can predict a requirement for central neck dissection (CND) in the clinically node negative (CNN) pediatric population. Retrospective chart review for pediatric patients who underwent thyroidectomy between 2014 and 2022. Patients were included if they had prior FNA with a result of: benign nodule, atypia or follicular neoplasm of undetermined significance (AUS/FNUS), follicular neoplasm (FN), or papillary thyroid carcinoma (PTC). All patients had intraoperative DLN analysis via frozen section histopathology. 27 patients were included, 9 males (33 %) and 18 females (67 %). On final pathology 19 patients (70.4 %) had PTC. The DLN was negative for carcinoma in all (n = 8, 100 %) patients with benign pathology. In 10 patients (100 %) with positive DLN on frozen section, postoperative pathology demonstrated central neck metastasis. Nine (90 %) of these patients were CNN and had alterations in the surgical plan based on the DLN. The tenth patient's surgical plan did not change given preoperative clinical disease. Three patients with negative DLNs had central neck metastasis. The DLN serves a role in guiding treatment for the pediatric population. Positive DLN altered surgical plans in 60 % of CNN PTC patients, allowing for CND to be performed and reducing need for additional surgical resection. The positive predictive value for DLN status was 100 % in this study, and the negative predictive value was 62.5 %. However, negative DLNs do not rule out central neck disease.
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Drug Discovery Landscape
5 orphan drug designations for Familial papillary or follicular thyroid carcinoma.
5 orphan drug designations for Familial papillary or follicular thyroid carcinoma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Larotrectinib sulfate [Vitrakvi] | small molecules | EMA | Bayer AG | |
Sorafenib tosilate [Nexavar] | small molecules | EMA | Bayer AG | |
Sorafenib tosilate [Nexavar] | small molecules | EMA | Bayer AG | |
Lenvatinib mesilate [Lenvima] | small molecules | EMA | Eisai GmbH | |
Lenvatinib mesilate [Lenvima] | small molecules | EMA | Eisai GmbH |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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