Thyroid Cancer Progression Research Articles

Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer

Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7/p21/BRAF/MAPK/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer.

YTHDF2 promotes anaplastic thyroid cancer progression by activating the DDIT4/AKT/mTOR signaling pathway

BackgroundRNA methylation, an important reversible post-transcriptional modification in eukaryotes, has emerged as a prevalent epigenetic alteration. However, the role of the m6A reader YTH domain family 2 (YTHDF2) has not been reported in anaplastic thyroid cancer (ATC) and its biological mechanism is unclear.MethodsThe relationship between YTHDF2 expression and ATC was determined using data sets and tissue samples. A range of analytical techniques were employed to investigate the regulatory mechanism of YTHDF2 in ATC, including bioinformatics analysis, m6A dot-blot analysis, methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, RNA sequencing, RNA stability assays and dual luciferase reporter gene assays. In vitro and in vivo assays were also conducted to determine the contribution of YTHDF2 to ATC development.ResultsYTHDF2 expression was significantly increased in ATC. The comprehensive in vitro and in vivo experiments demonstrated that YTHDF2 knockdown significantly attenuated ATC proliferation, invasion, migration, and apoptosis promotion, whereas YTHDF2 overexpression yielded the opposite trend. Mechanistically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrated that YTHDF2 accelerated the degradation of DNA damage-inducible transcript 4 or regulated in DNA damage and development 1 (DDIT4, or REDD1) mRNA in an m6A-dependent manner, which in turn activated the AKT/mTOR signaling pathway and induced activation of epithelial-mesenchymal transition (EMT), thereby promoting ATC tumor progression.ConclusionsThis study is the first to demonstrate that elevated YTHDF2 expression levels suppress DDIT4 expression in an m6A-dependent manner and activate the AKT/mTOR signaling pathway, thereby promoting ATC progression. YTHDF2 plays a pivotal role in ATC progression, and it may serve as a promising therapeutic target in the future.

Multimodal separation and cross fusion network based on Raman spectroscopy and FTIR spectroscopy for diagnosis of thyroid malignant tumor metastasis

The diagnosis of cervical lymph node metastasis from thyroid cancer is an essential stage in the progression of thyroid cancer. The metastasis of cervical lymph nodes directly affects the prognosis and survival rate of patients. Therefore, timely and early diagnosis is crucial for effective treatment and can significantly improve patients’ survival rate and quality of life. Traditional diagnostic methods, such as ultrasonography and radionuclide scanning, have limitations, such as complex operations and high missed diagnosis rates. Raman spectroscopy and FTIR spectroscopy can well reflect the molecular information of samples, have characteristics such as sensitivity and specificity, and are simple to operate. They have been widely used in clinical research in recent years. With the development of intelligent medical diagnosis technology, medical data shows a multi-modal trend. Compared with single-modal data, multi-modal data fusion can achieve complementary information, provide more comprehensive and valuable diagnostic information, significantly enhance the richness of data features, and improve the modeling effect of the model, helping to achieve better results. Accurate disease diagnosis. Existing research mostly uses cascade processing, ignoring the important correlations between multi-modal data, and at the same time not making full use of the intra-modal relationships that are also beneficial to prediction. We developed a new multi-modal separation cross-fusion network (MSCNet) based on deep learning technology. This network fully captures the complementary information between and within modalities through the feature separation module and feature cross-fusion module and effectively integrates Raman spectrum and FTIR spectrum data to diagnose thyroid cancer cervical lymph node metastasis accurately. The test results on the serum vibrational spectrum data set of 99 cases of cervical lymph node metastasis showed that the accuracy and AUC of a single Raman spectrum reached 63.63% and 63.78% respectively, and the accuracy and AUC of a single FTIR spectrum reached 95.84% respectively and 96%. The accuracy and AUC of Raman spectroscopy combined with FTIR spectroscopy reached 97.95% and 98% respectively, which is better than existing diagnostic technology. The omics correlation verification obtained correlation pairs of 5 Raman frequency shifts and 84 infrared spectral bands. This study provides new ideas and methods for the early diagnosis of cervical lymph node metastasis of thyroid cancer.

Correction: Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression

Correction: Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression

Exploring exosomes: novel diagnostic and therapeutic frontiers in thyroid cancer.

In recent years, the incidence of thyroid cancer has surged globally, posing significant challenges in its diagnosis, treatment, and prognosis. Exosomes, as a class of extracellular vesicles, are secreted by nearly all cell types and encapsulate a variety of nucleic acids and proteins reflective of their cell of origin, thereby facilitating critical intercellular communication. Recent advancements in understanding these exosomes have catalyzed their application in oncology, particularly through uncovering their roles in the pathogenesis, diagnosis, and therapy of cancers. Notably, the latest literature highlights the integral role of exosomes in refining diagnostic techniques, enhancing targeted therapies, optimizing radiotherapy outcomes, and advancing immunotherapeutic approaches in thyroid cancer management. This review provides a current synthesis of the implications of exosomes in thyroid cancer tumorigenesis and progression, as well as their emerging applications in diagnosis and treatment strategies. Furthermore, we discuss the profound clinical potential of exosome-based interventions in managing thyroid cancer, serving as a foundational reference for future therapeutic developments.

Study on association between human plasma polybrominated diphenyl ethers (PBDEs) and thyroid homeostasis and carcinoma.

Polybrominated diphenyl ethers (PBDEs), a category of persistent organic pollutants (POPs), are ubiquitous in the environment and have been reported to have endocrine-disrupting and tumor-promoting activities. However, the evidence for the correlation between plasma PBDEs levels, thyroid homeostasis and thyroid carcinoma in humans remains limited. Herein, we analyzed eight PBDE congeners in 53 patients undergoing thyroid surgery. BDE-209 was identified as the most abundant PBDE congener in plasma (median, 11.36ng/g lipid). BDE-100 concentration was positively associated with free triiodothyronine (FT3), indicating a potential interference with thyroid function. Point-biserial correlation analysis revealed positive associations between certain plasma PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, and BDE-154) and aggressive pathological parameters. There was no significant correlation between PBDEs and BRAF or RAS mutations in PTC patients, indicating that PBDEs may not directly promote the initiation and progression of thyroid cancer through these genetic mutations. It implies the complexity of the relationship between PBDEs exposure and thyroid cancer development. Although not statistically significant, Bayesian kernel-machine regression (BKMR) analysis of single-exposure effects model found that BDE-47 and BDE-99 were positively associated with the risk of malignant neoplasms. The present study not only contributes to the growing evidence regarding the impact of PBDEs on thyroid function but also provides new insights into the association between exposure to certain PBDE congeners and the aggressive pathological parameters of thyroid cancer. Large-scale prospective studies are still needed to support our findings.

TM4SF4 is a diagnostic biomarker accelerating progression of papillary thyroid cancer via AKT pathway.

The incidence of papillary thyroid cancer (PTC) has been steadily rising, though the underlying mechanism remains unclear. This study aims to elucidate the biological role of TM4SF4 in the PTC progression. Our differential expression analysis indicated that TM4SF4 was significantly upregulated in PTC, which was corroborated in both our local cohort and the data from Human Protein Atlas. Additionally, clinical characteristics analysis and receiver operating characteristic curves (ROC) demonstrated that TM4SF4 served as a significant diagnostic marker for PTC. Correlation and enrichment analysis of TM4SF4-related partners suggested that it was involved in cell junction and cohesion processes. Furthermore, immune infiltration analysis revealed a positive correlation between TM4SF4 expression and the immune activation in PTC. Importantly, in vitro experiments demonstrated that TM4SF4 downregulation suppressed the proliferation and metastasis of PTC cell lines while inducing apoptosis. We further discovered that the AKT activator SC79 was able to reverse the malignant behaviors suppression caused by TM4SF4 knockdown, suggesting that TM4SF4 may promote PTC progression via the AKT pathway. In conclusion, our study highlights the oncogenic role of TM4SF4 in PTC and identifies it as a novel biomarker for diagnosis and treatment.

The Horizon of Thyroid Imaging Reporting and Data System in the Diagnostic Performance of Thyroid Nodules: Clinical Application and Future Perspectives.

The widespread occurrence of thyroid nodules and the typically slow progression of thyroid cancer have led to the development of the thyroid imaging reporting and data system (TI-RADS). The primary objectives behind the development of TI-RADS were to minimize unnecessary biopsies of non-cancerous nodules, enhance the overall precision of diagnosis and establish a uniform risk-stratification framework based on the lexicon to notify healthcare professionals of nodules that require a biopsy. The identification and precise diagnosis of thyroid nodules have led to improved clinical practice examination reports within the general population. TI-RADS is a risk-stratification system related to thyroid lesions and based on ultrasound characteristics and is similar to the structure of the breast imaging reporting and data system. There are various versions of TI-RADS, with some being widely used and adequately validated, while others lacking thorough evaluation. TI-RADS uses a numerical scoring system for characteristics, and its categories are determined by the cumulative score of a thyroid nodule, indicating the likelihood of it being benign or malignant. In this article, the various TI-RADS systems were examined as a successful method for producing precise and comprehensive documentation, with a particular emphasis on their functionality, similarities, distinctions and potential future developments.

METTL14-mediated m6A modification upregulated SOCS3 expression alleviates thyroid cancer progression by regulating the JAK2/STAT3 pathway

Thyroid cancer (TC) is the most common malignant tumor of the head and neck. As a common epigenetic modification in mRNAs, N6-methyladenosine (m6A) modification plays critical roles in biological process of cancers. However, m6A methyltransferase methyltransferase-like 14 (METTL14)-mediated m6A modification and its potential regulatory mechanisms in TC are not fully elucidated. In our study, we observed that METTL14 was decreased in TC tissues and cells. And upregulation of METTL14 induced apoptotic cell death and hampered cell proliferation, epithelial mesenchymal transition (EMT) and tumor growth in vitro and in vivo. Mechanistically, METTL14 increased the expression of suppressor of cytokine signaling 3 (SOCS3) through m6A methylation modification, and knockdown of SOCS3 reversed the inhibitory effect of overexpressing METTL14 on TC tumorigenesis. In addition, METTL14-mediated m6A modification of SOCS3 inactivated the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway, and in the METTL14-overexpressing TC cells, silencing SOCS3-induced upregulation of cell proliferation, EMT and suppression of apoptosis was reversed by JAK2/STAT3 inhibitor AG490 and WP1066. Together, we indicated that METTL14/m6A/SOCS3/JAK2/STAT3 axis play an important role in the progression of TC.

Identification of potential biomarkers of papillary thyroid carcinoma.

This study aimed to identify candidate biomarkers for papillary thyroid carcinoma using an integrative analysis of bioinformatics and machine learning (ML). The PTC datasets GSE6004, GSE3467, and GSE33630 (species: Homo sapiens) were downloaded from NCBI and analyzed using the limma package to obtain DEGs. Once DEGs were identified, GO and KEGG enrichment analyses were performed as the first step in the bioinformatics process. Subsequently, a protein-protein interaction (PPI) network was constructed according to the common genes in bioinformatics and machine learning using STRING to elucidate the important genes involved in PTC pathogenesis. In machine learning, finding genes entails feature selection to identify the key genes that distinguish biological states. Hybrid feature selection will be used for this. In the second step, the original data sets were preprocessed to detect and correct missing and noisy data; after that, all data were merged. Following performing Linear and Discriminative Hybrid Feature Selection (LDHFS) on the processed dataset, machine learning algorithms such as Random Forest (RF), Naive Bayes (NB), and Support Vector Machines (SVM) are utilized. Bioinformatics and machine learning analyses indicate that the genes RXRG, CDH2, ETV5, QPCT, LRP4, FN1, and LPAR5 are integral to the progression of thyroid cancer. This study attained the highest accuracy utilizing the RF algorithm, achieving an accuracy rate of 94.62%, a Kappa value of 91.36%, and an AUC value of 96.13%. These results offer additional evidence and confirmation for the genetic alterations of these genes. These findings may accelerate the development of prospective therapeutic and diagnostic methods in future research. Bioinformatics and machine learning techniques identified the common genes "RXRG, CDH2, ETV5, QPCT, LRP4, FN1, and LPAR5" as PTC biomarkers, providing novel reference markers for the diagnosis and treatment of PTC patients. The model is anticipated to possess significant predictive value and assist in the early diagnosis and screening of clinical PTC. These insights enhance the field of PTC management and offer guidance for future research.

6897 The Role of Neutrophil Heterogeneity on T-cell Immunity in Advanced Thyroid Cancer Patients

Abstract Disclosure: Y. Kang: None. S. Lee: None. J. Yoon: None. D. Kang: None. J. Lee: None. Neutrophil heterogeneity is involved in autoimmune diseases, sepsis, and several cancers. However, the link between neutrophil heterogeneity and T-cell immunity in thyroid cancer is incompletely understood. We investigated the circulating neutrophil heterogeneity in 3 undifferentiated thyroid cancer (UTC), 14 differentiated thyroid cancer (DTC) (4 Stage IV, 10 Stage I-II), and healthy controls (n=10) by transcriptomic data and cytometry. Participants with UTC had a significantly higher proportion of immature high-density neutrophils (HDN) and lower proportion of mature HDN in peripheral blood compared to DTC. The proportion of circulating PD-L1+ immature neutrophils were significantly increased in advanced cancer patients. Unsupervised analysis of transcriptomics data from circulating HDN revealed downregulation of innate immune response and T cell receptor signaling pathway in cancer patients. Moreover, UTC patients revealed the upregulation of glycolytic process and glutamate receptor signaling pathway. Comparative analysis across tumor types and stages revealed the downregulation of various T cell related pathways, such as T cell receptor signaling pathway and T cell proliferation in advanced cancer patients. Moreover, the proportions of CD8+ and CD4+ T effector memory CD45RA+ (TEMRA) cells from peripheral blood were significantly decreased in UTC patients compared to DTC patients. Finally, we demonstrated that proportions of tumor infiltrated neutrophils were increased and related with poor prognosis in advanced thyroid cancer using data from our RNA-seq and TCGA (The Cancer Genome Atlas) data. In conclusion, observed prevalence of circulating immature high-density neutrophils and their immunosuppressive features in undifferentiated thyroid cancers underscore the importance of understanding neutrophil dynamics in the context of tumor progression in thyroid cancer. Presentation: 6/3/2024

7092 Blocking of Aggressive Tumor Progression of Anaplastic Thyroid Cancer by p53

Abstract Disclosure: E. Hwang: None. R. Chari: None. T. Kimura: None. S. Cheng: None. Background: Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer, with very limited treatment options. Patients succumb to death within 6-12 months after diagnosis. It has been observed that mutations of p53, occurring as tumorigenesis progresses, is associated with the aggressiveness of ATC. The present studies tested the hypothesis that wild type p53 (WTp53) could block tumor progression and mitigate its aggressiveness. Methods: We used human 8505C cells as a model, derived from human ATC tumors, harboring BRAFV600E mutation and one allele of mutated p53C742G. We re-expressed WTp53 or mutant p53C742G into 8505C cells (8505C-WTp53 or 8505C-MTp53 cells, respectively) via lentiviral transduction. We analyzed the effects of exogenous expressed WTp53 and mutant p53 on cell proliferation, apoptosis, and migration in vitro and the progression of tumors in vivo mouse xenograft models. Results: We showed that p53 proteins were more abundantly expressed in 8505C-WTp53 or 8505C-MTp53 cells than the parental 8505C cells. Using WTp53 luciferase reporter (PG-13), we demonstrated that the expressed WTp53 was functional as the transcription activity of p53 was higher than the parental 8505C cells. Consistently, in 8505C-MTp53, the reporter activity of PG-13 was not detected. The expressed WTp53 inhibited cell proliferation and decreased cell migration. Immunohistochemical analysis (IHC) showed decreased proliferation marker Ki67 and increased cleaved caspase-3, indicating the induction of apoptosis in 8505C-WTp53 cells. Importantly, we found that the NIS expression was increased in 8505C-WTp53 cells, but not in 8505C-MTp53 cells, as compared with 8505C cells. Xenograft studies showed that tumor progression was inhibited in nude mice injected with 8505C-WTp53 cells as compared with tumors induced by 8505C parental cells and 8505C-MTp53 cells. Consistent with in vitro findings, IHC demonstrated decreased proliferation marker Ki67 and increased cleaved caspase-3 proteins in tumors induced by 8505C-WTp53 cells. Furthermore, the expression of apoptotic regulators such as BAX and PUMA, known as p53 target genes, were elevated in 8505C-WTp53 cultured cells and in 8505C-WTp53-induced tumors, indicating induction of apoptosis. Conclusions: Our findings showed that the aggressiveness of ATC, caused by mutant p53 in late stage of tumor progression, can be mitigated by exogenous expression of WTp53. These results provided new insights into the deleterious actions of mutation of p53 in ATC tumor development. Importantly, our studies revealed that targeting p53 in ATC could be considered as a potential therapeutic opportunity. Presentation: 6/3/2024

ZNF217 Mediates Transcriptional Activation of GRHL3 to Regulate SLC22A31 and Promote Malignant Progression in Thyroid Cancer.

The incidence of thyroid cancer (THCA) has increased worldwide during the past 40 years. However, an understanding of the mechanisms and major transcription factors involved in THCA is insufficient to identify therapeutic targets against THCA. To reveal such mechanisms, we conducted bioinformatics analyses to assess the differential expression in human THCA sample and normal tissue sample, leading us to focus on the function of the ZNF217/GRHL3/ SLC22A31 axis in mediating biological activity in THCA. The genes of interest were interfered with lentiviral vectors, and transfection efficiency was verified using RT-qPCR. ZNF217, GRHL3, and SLC22A31 were abundantly expressed in THCA tissues or cells. Knockdown of GRHL3, ZNF217, or SLC22A31 all significantly curtailed the malignant biological behavior of THCA cells. ZNF217 promoted GRHL3 expression through transcriptional activation, thereby increasing the transcription of SLC22A31. Ectopic expression of GRHL3 or SLC22A31 abated the suppressing impact of ZNF217 or GRHL3 knockdown on the biological activity of THCA cells. Collectively, our results demonstrated that ZNF217 acted as an activator of GRHL3, thereby promoting the expression of SLC22A31 and the malignant activity of THCA cells.

Investigating the mechanism of METTL16-dependent m6A modification regulating the SAMD11 protein signaling pathway to inhibit thyroid cancer phenotypes

Despite substantial progress in the research and treatment of thyroid cancer, many areas in the molecular mechanisms remain to be explored. This study aims to comprehensively and deeply investigate the key role and potential molecular mechanisms of RNA methyltransferase METTL16 in the development and progression of thyroid cancer. Firstly, through bioinformatics analysis of tumor databases, we examined the correlation between METTL16 expression levels and patient prognosis. Subsequently, immunofluorescence experiments on clinical patient tissue microarrays were conducted to validate these findings. We also compared the nucleic acid and protein expression levels of METTL16 in different cell lines. By integrating bioinformatics analysis of public databases, laboratory molecular biology experiments, and comprehensive data analysis, we revealed the high expression of METTL16 in clinical tissues and thyroid cancer cells, and confirmed its role in regulating the biological characteristics of cell proliferation, migration, and invasion in thyroid cancer through in vitro and in vivo experiments. Additionally, we identified SAMD11 as a target gene of METTL16 and further validated its importance and potential regulatory pathways in thyroid cancer.

Potential functions and mechanisms of lysine crotonylation modification (Kcr) in tumorigenesis and lymphatic metastasis of papillary thyroid cancer (PTC).

To examine the putative functions and mechanisms of lysine crotonylation (Kcr) during the development and progression of papillary thyroid cancer (PTC). Samples of thyroid cancer tissues were collected and subjected to liquid chromatography-tandem mass spectrometry. Crotonylated differentially expressed proteins (DEPs) and differentially expressed Kcr sites (DEKSs) were analyzed by Motif, dynamic expression model analysis (Mfuzz), subcellular localization, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, Go Ontology (GO) annotation, and protein-protein interaction analysis (PPI). Validation was performed by immunohistochemistry (IHC). A total of 262 crotonylated DEPs and 702 DEKSs were quantitated. First, for the tumor/normal comparison, a dynamic expression model analysis (Mfuzz) of the DEKSs revealed that clusters 1, 3, and 4 increased with the progression of thyroid cancer; however, cluster 6 showed a dramatic increase during the transition from N0-tumor to N1-tumor. Furthermore, based on GO annotation, KEGG, and PPI, the crotonylated DEPs were primarily enriched in the PI3K-Akt signaling pathway, Cell cycle, and Hippo signaling pathway. Of note, crosstalk between the proteome and Kcr proteome suggested a differential changing trend, which was enriched in Thyroid hormone synthesis, Pyruvate metabolism, TCA cycle, Cell cycle, and Apoptosis pathways. Similarly, for the LNM comparison group, the DEKSs and related DEPs were primarily enriched in Hydrogen peroxide catabolic process and Tight junction pathway. Finally, according to The Cancer Genome Atlas Program (TCGA) database, the differential expression of Kcr DEPs were associated with the prognosis of thyroid cancer, indicating the prognostic significance of these proteins. Moreover, based on the clinical validation of 47 additional samples, Kcr was highly expressed in thyroid tumor tissues compared with normal tissue (t = 9.792, P < 0.001). In addition, a positive correlation was observed between Kcr and N-cadherin (r = 0.5710, P = 0.0015). Moreover, N-cadherin expression was higher in the relatively high Kcr expression group (χ2 = 18.966, P < 0.001). Higher Kcr expression was correlated with thyroid tumorigenesis and lymphatic metastasis, which may regulate thyroid cancer progression by Pyruvate metabolism, TCA cycle, Cell cycle, and other pathways.

IPLA2β regulates the dual effects of arachidonic acid in thyroid cancer.

Abnormal arachidonic acid metabolism in the tumor microenvironment is closely related to cancer progression; however, thyroid cancer was rarely researched. Through lipidomic analysis, we disclosed that dysregulated arachidonic acid metabolism plays dual effects on thyroid cancer. The promoting role of arachidonic acid in the progression of thyroid cancer cells was evaluated utilizing cell viability (CCK-8 assay) and transwell invasion assays, confirmed by corresponding inhibitors. Lipid peroxidation and the use of various cell death inhibitors confirmed that arachidonic acid confers vulnerability to ferroptosis in thyroid cancer. The roles of arachidonic acid and ferroptosis inducer in thyroid cancer were assessed in a xenograft mouse model. On one hand, arachidonic acid promotes the progression of thyroid cancer through the cyclooxygenase/prostaglandin pathway; on another hand, arachidonic acid confers vulnerability to ferroptosis through lipoxygenases. Moreover, iPLA2β drives converse roles of arachidonic acid between cancer-progression and ferroptosis vulnerability through releasing free arachidonic acid from the cell membrane. Finally, we confirmed high arachidonic acid diet promotes the development of thyroid cancer in vivo, whereas ferroptosis inducer sulfasalazine dramatically reduced tumor growth of mice with feeding arachidonic acid. Our research demonstrated the roles of iPLA2β in conversing dual effects of arachidonic acid in thyroid cancer and provides ferroptosis inducer as a potential therapeutic strategy.

Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression

Thyroid cancer is the most frequently observed endocrine-related malignancy among which anaplastic thyroid cancer (ATC) is the most fatal subtype. The synthesis of protein is active to satisfy the rapid growth of ATC tumor, but the mechanisms regulating protein synthesis are still unknown. Our research revealed that kinetochore protein NUF2 played an essential role in protein synthesis and drove the progression of ATC. The prognosis of patients with thyroid carcinoma was positively correlated with high NUF2 expression. Depletion of NUF2 in ATC cells notably inhibited the proliferation and induced apoptosis, while overexpression of NUF2 facilitated ATC cell viability and colony formation. Deletion of NUF2 significantly suppressed the growth and metastasis of ATC in vivo. Notably, knockdown of NUF2 epigenetically inhibited the expression of magnesium transporters through reducing the abundance of H3K4me3 at promoters, thereby reduced intracellular Mg2+ concentration. Furthermore, we found the deletion of NUF2 or magnesium transporters significantly inhibited the protein synthesis mediated by the PI3K/Akt/mTOR pathway. In conclusion, NUF2 functions as an emerging regulator for protein synthesis by maintaining the homeostasis of intracellular Mg2+, which finally drives ATC progression.

MAZ promotes thyroid cancer progression by driving transcriptional reprogram and enhancing ERK1/2 activation

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancies worldwide. Oncogenic transcription factors (TFs) drive transcriptional reprogramming and tumorigenesis. The myc-associated zinc finger protein (MAZ) is one of the Myc family TFs. The role of MAZ in PTC pathogenesis is still largely unknown. Here, we report that MAZ profoundly promotes proliferation of PTC cells ex vivo and in vivo through activating MAPK signaling. We firstly profiled gene expression of PTC cells after silencing of MAZ. BRAF, KRAS and LOC547 were identified as important target genes of TF MAZ. In particular, TF MAZ bound to the promoters of BRAF or KRAS and significantly increased their transcription and expression levels. Meanwhile, MAZ could noticeably elevate LOC547 transcription and expression as a TF. High levels of LOC547 relocated ACTN4 protein from the nucleus to the cytosol, improved protein-protein interactions between ACTN4 and EGFR in the cytosol, enhanced ERK1/2 phosphorylation, activated the MAPK signaling and, thus, promoted PTC progression. Our data identify a previously underappreciated MAZ-controlled transcriptional reprogram and ERK1/2 activation via BRAF, KRAS and LOC547. Our data illustrate that activation of the MAZ-controlled axis promotes thyroid tumorigenesis. These insights would advance our knowledge of the role of TFs in cancer development and highlight the potential of TFs as future targets for treatments against cancers.

FN1, a reliable prognostic biomarker for thyroid cancer, is associated with tumor immunity and an unfavorable prognosis.

Thyroid cancer (THCA) is a malignant tumor that affects the endocrine system. At present, an effective treatment for THCA remains elusive, particularly for medullary carcinoma and undifferentiated carcinoma, due to the lack of suitable medications and prognostic markers. Patient RNA-sequencing and clinical data were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Protein-protein interaction analyses were performed for differentially expressed genes related to THCA. Moreover, the associations between fibronectin 1 (FN1), clinical data, immune checkpoint genes and immune cell infiltration was assessed. The potential functional role of the FN1 gene was evaluated through gene set enrichment analysis. Immunohistochemistry was used to assess FN1 expression in 103 cases of THCA, comprising 32 with papillary carcinoma, 30 with follicular carcinoma, 35 with medullary carcinoma and 6 with undifferentiated carcinoma. Finally, 11 co-expression modules were constructed and the expression of five identified hub genes (FN1, mucin-1, keratin 19, intracellular adhesion molecule 1 and neural cell adhesion molecule) were evaluated. The results demonstrated that higher FN1 gene expression levels were strongly associated with a higher pathologic stage and tumor stage, and were significantly associated with immune cell infiltration in THCA. Significant increases in FN1 protein expression levels were noted among patients diagnosed with four types of THCA, comprising papillary carcinoma, follicular carcinoma, medullary carcinoma and undifferentiated carcinoma. Patients diagnosed with medullary carcinoma and undifferentiated carcinoma, and with low FN1 expression levels, exhibited a significant survival advantage compared with those with high FN1 expression levels. In conclusion, the present study identified five hub genes involved in the onset and progression of THCA. Furthermore, FN1 could serve as a candidate biomarker and a therapeutic target for THCA and may be a key gene mediating THCA immune infiltration.

Role of the oncogene UHRF1 in thyroid cancer differentiation, progression and response to lenvatinib

Role of the oncogene UHRF1 in thyroid cancer differentiation, progression and response to lenvatinib