Prognosis Of Papillary Thyroid Cancer Research Articles

A New Ferroptosis-Related Long Non-Coding RNA Risk Model Predicts the Prognosis of Patients With Papillary Thyroid Cancer.

Ferroptosis is a novel form of regulated cell death that involves in cancer progression. However, the role of ferroptosis-related long non-coding RNAs (lncRNAs) in papillary thyroid cancer (PTC) remains to be elucidated. The purpose of this paper was to clarify the prognostic value of ferroptosis-related lncRNAs in PTC. The transcriptome data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between ferroptosis-related genes (FRGs) and lncRNA was determined using Pearson correlation analysis. Multivariate Cox regression model (P < 0.01) was performed to establish a ferroptosis-related lncRNAs risk model. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, risk curve and nomograms were then performed to assess the accuracy and clinical applicability of prognostic models. The correlations between the prognosis model and clinicopathological variables, immune and m6A were analyzed. Finally, in vitro assays were performed to verify the role of LINC00900, LINC01614 and PARAL1 on the proliferation, migration and invasion in TPC-1 and BCPAP cells, as well as the relationship between three lncRNAs and ferroptosis. A five-ferroptosis-related lncRNAs (PARAL1, LINC00900, DPH6-DT, LINC01614, LPP-AS2) risk model was constructed. Based on the risk score, samples were divided into the high- and low-risk groups. Patients in the low-risk group had better prognosis than those in high-risk group. Compared to traditional clinicopathological features, risk score was more accurate in predicting prognosis in patients with PTC. Additionally, the difference of immune cell, function and checkpoints was observed between two groups. Moreover, experiments showed that LINC00900 promoted the proliferation, migration and invasion in TPC-1 and BCPAP cells, while LINC01614 and PARAL1 revealed opposite effects, all of which were related to ferroptosis. In summary, we identified a five-ferroptosis-related lncRNAs risk model to predict the prognosis of PTC. Furthermore, our study also revealed that LINC00900 functioned as a tumor suppressor lncRNA, LINC01614 and PARAL1 as an oncogenic lncRNA in PTC.

Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma

BackgroundThe incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10–15% of the patients have a poor prognosis. Although immunotherapy has been applied in clinical practice,...

Network Pharmacological Analysis and Experimental Validation of the Effects of Silybin on Proliferation, Migration, and Immunotherapy of Papillary Thyroid Cancer.

The study aimed to use network pharmacology research and in vitro experiments to investigate the material basis and molecular mechanisms of silybin in the treatment of papillary thyroid carcinoma. Papillary thyroid cancer (PTC) has a decent prognosis; however, recurrence and metastasis are the leading causes of death in patients with PTC. A key research focus in thyroid cancer treatment is the inhibition of PTC proliferation, invasion, and migration. Silybin, the major active element in the traditional Chinese herb silymarin, has been used to treat a range of diseases, including cancer, but no study has been undertaken to determine whether it can help prevent PTC. In this study, we attempted to determine through network pharmacology and in vitro experiments if silybin inhibits the development of papillary thyroid cancer by inhibiting cell cycle and invasive migration. To predict the probable targets and underlying mechanisms of silybin against PTC, a network pharmacology research was performed. In vitro experiments were conducted to further evaluate silybin's anti-cancer properties and priority targets against PTC. The datasets revealed a total of 489 silybin targets acting on PTC, and functional enrichment analysis suggested that the target genes were enriched in functions and pathways related to PTC development, invasion, migration, and immunotherapy. By constructing these target PPI networks, the seven hub genes, fibronectin 1 (FN1), tissue inhibitor of metalloproteinases 1 (TIMP1), N-cadherin (CDH2), collagen type III alpha 1 chain (COL3A1), cyclin D1 (CCND1), AP-1 transcription factor subunit (JUN), and hepatocyte growth factor receptor (MET) were found. These hub genes were determined to be highly linked to a worse clinicopathological form, a higher risk of metastatic recurrence, and a worse prognosis of PTC. The common immunological checkpoint gene expression levels were positively correlated with the expression levels of the hub genes. Silybin decreased the proliferative and metastatic capacity of PTC cells, according to in vitro investigations. When PTC was treated with silybin, the FN1/AKT signaling pathway was blocked, CCND1 expression was reduced, and CDH2, Vimentin, Snail, Slug and PD-L1 expressions were dramatically reduced, while E-cadherin expression was significantly elevated. These findings provide preliminary evidence that silybin inhibits PTC cell proliferation, metastasis, and invasion by altering the FN1/AKT signaling pathway and inhibiting the EMT process. Silybin can reverse immunosuppression in papillary thyroid cancer by affecting immunological checkpoint gene expression levels. These studies provide a theoretical and experimental scientific basis for the potential anticancer effects of silybin on PTC.

Identification and validation of an anoikis-related genes signature for prognostic implication in papillary thyroid cancer.

Thyroid cancer, notably papillary thyroid cancer (PTC), is a global health concern with increasing incidence. Anoikis, a regulator of programmed cell death, is pivotal in normal physiology and, when dysregulated, can drive cancer progression and metastasis. This study explored the impact of anoikis on PTC prognosis. Analyzing data from GEO, TCGA, and GeneCards, we identified a prognostic signature consisting of six anoikis-related genes (ARGs): EZH2, PRKCQ, CD36, INHBB, TDGF1, and MMP9. This signature independently predicted patient outcomes, with high-risk scores associated with worse prognoses. A robust predictive ability was confirmed via ROC analysis, and a nomogram achieved a C-index of 0.712. Differences in immune infiltration levels were observed between high- and low-risk groups. Importantly, the high-risk group displayed reduced drug sensitivity and poor responses to immunotherapy. This research provides insights into anoikis in PTC, offering a novel ARG signature for predicting patient prognosis and guiding personalized treatment strategies.

“Examining the link between tooth agenesis and papillary thyroid cancer: is there a risk factor?” Observational study

BackgroundMutations in one or multiple genes can lead to hypodontia and its characteristic features. Numerous studies have shown a strong genetic influence on the occurrence of hypodontia, and identified several genes, including AXIN2, EDA, FGF3, FGFR2, FGFR10, WNT10A, MSX1, and PAX9, that are directly associated with dental agenesis and carcinogenesis. The objective of this study was to investigate the occurrence and pattern of tooth agenesis, microdontia, and palatally displaced canine (PDC) in women diagnosed with papillary thyroid cancer (PTC), compared to a control group of women without any malignancy or thyroid disease.Materials and methodsThis case–control study was carried at the Department of Orthodontics, School of Dental Medicine University of Zagreb, and Department of Oncology and Nuclear Medicine Sestre Milosrdnice University Hospital Centre. The study involved a clinical examination and evaluation of dental status, panoramic X-ray analysis, and assessment of medical and family history of 116 female patients aged 20–40 with PTC, as well as 424 females in the control group who were of similar age.ResultsThe prevalence of hypodontia, microdontia, and PDC was statistically higher in women with PTC than in the control group. The prevalence rate of hypodontia was 11.3% in the experimental group and 3.5% in the control group. The experimental group showed a higher occurrence of missing upper lateral incisors, lower left central incisors, and all the third molars (except the upper left) compared to the control group. Women with PTC showed the prevalence of PDC significantly higher than the control group (3.5%, 0.7%, p = 0.002). The probability of hypodontia as a clinical finding increases 2.6 times, and microdontia occurs 7.7 times more frequently in women with PTC.ConclusionOur study suggests a possible link between odontogenesis and PTC. The absence of permanent teeth may increase the likelihood of PTC in women. Leveraging the age-7 orthopantomogram to identify women at high risk for PTC within a critical early detection window could significantly improve oral health outcomes and PTC prognosis through proactive interventions.

Cytosolic Cadherin 4 promotes angiogenesis and metastasis in papillary thyroid cancer by suppressing the ubiquitination/degradation of β-catenin

BackgroundAlthough the long-term prognosis of papillary thyroid cancer (PTC) is favorable, distant metastasis significantly compromises the prognosis and quality of life for patients with PTC. The Cadherin family plays a pivotal role in tumor metastasis; however, the involvement of Cadherin 4 (CDH4) in the metastatic cascade remains elusive.MethodsThe expression and subcellular localization of CDH4 were determined through immunohistochemistry, immunofluorescence, and western blot analyses. The impact of CDH4 on cell migration, invasion, angiogenesis, and metastasis was assessed using transwell assays, tube formation assays, and animal experiments. Immunoprecipitation assay and mass spectrometry were employed to examine protein associations. The influence of CDH4 on the subcellular expression of β-catenin and active β-catenin was investigated via western blotting and immunofluorescence. Protein stability and ubiquitination assay were employed to verify the impact of CDH4 on β-catenin degradation. Rescue experiments were performed to ensure the significance of CDH4 in regulating nuclear β-catenin signaling.ResultsCDH4 was found to be significantly overexpressed in PTC tissues and predominantly localized in the cytoplasm. Furthermore, the overexpression of CDH4 in tumor tissues is associated with lymph node metastasis in PTC patients. Cytosolic CDH4 promoted the migration, invasion, and lung metastasis of PTC cells and stimulated the angiogenesis and tumorigenesis of PTC; however, this effect could be reversed by Tegavivint, an antagonist of β-catenin. Mechanistically, cytosolic CDH4 disrupted the interaction between β-catenin and β-TrCP1, consequently impeding the ubiquitination process of β-catenin and activating the nuclear β-catenin signaling.ConclusionsCDH4 induces PTC angiogenesis and metastasis via the inhibition of β-TrCP1-dependent ubiquitination of β-Catenin.

TERT promoter methylation is associated with high expression of TERT and poor prognosis in papillary thyroid cancer.

The telomerase reverse transcriptase (TERT) is overexpressed and associated with poor prognosis in papillary thyroid cancer (PTC), the most common subtype of thyroid cancer. The overexpression of TERT in PTC was partially attributed to transcriptional activation by two hotspot mutations in the core promoter region of this gene. As one of the major epigenetic mechanisms of gene expression regulation, DNA methylation has been proved to regulate several tumor-related genes in PTC. However, the association of TERT promoter DNA methylation with TERT expression and PTC progression is still unclear. By treating PTC cell lines with demethylating agent decitabine, we found that the TERT promoter methylation and the genes' expression were remarkably decreased. Consistently, PTC patients with TERT hypermethylation had significantly higher TERT expression than patients with TERT hypomethylation. Moreover, TERT hypermethylated patients showed significant higher rates of poor clinical outcomes than patients with TERT hypomethylation. Results from the cox regression analysis showed that the hazard ratios (HRs) of TERT hypermethylation for overall survival, disease-specific survival, disease-free interval (DFI) and progression-free interval (PFI) were 4.81 (95% CI, 1.61-14.41), 8.28 (95% CI, 2.14-32.13), 3.56 (95% CI, 1.24-10.17) and 3.32 (95% CI, 1.64-6.71), respectively. The HRs for DFI and PFI remained significant after adjustment for clinical risk factors. These data suggest that promoter DNA methylation upregulates TERT expression and associates with poor clinical outcomes of PTC, thus holds the potential to be a valuable prognostic marker for PTC risk stratification.

Establishment and validation of a novel risk model based on CD8T cell marker genes to predict prognosis in thyroid cancer by integrated analysis of single-cell and bulk RNA-sequencing.

Papillary thyroid cancer (PTC) is a histological type of thyroid cancer, and CD8T is important for the immune response. The single-cell RNA data were acquired from Gene Expression Omnibus. SingleR package was used for cluster identification, and CellChat was exploited to evaluate the interaction among several cell types. Bulk RNA data obtained from the cancer genome atlas were used for determination of prognosis using Kaplan-Meier and Receiver Operating Characteristic curve. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were applied for assessment of function enrichment. The drug sensitivity was calculated in Gene Set Cancer Analysis. The regulatory network was constructed by STRING and Cytoscape. We identified 23 cell clusters and 10 cell types. Cell communication results showed CD8T cell was vital among all immune cell types. Enrichment analysis found the marker genes of CD8T cell was enriched in some signal pathways related to tumor development. Overall, FAM107B and TUBA4A were considered as hub genes and used to construct a risk model. Most immune checkpoint expressions were upregulated in tumor group. Tumor mutation burden results indicated that prognosis of PTC was not related to the mutation of hub genes. Drug sensitivity analysis showed some drugs could be effectively used for the treatment of PTC, and regulatory network identified some targets for the immunotherapy. A 2-gene model of PTC was developed based on the single-cell RNA and bulk RNA data. Besides, we found CD8T was essential for the immune response in PTC.

TTK is a potential regulator of tumor progression correlated with dedifferentiation and immune cell infiltration in papillary thyroid cancer.

To investigate the role and clinical significance of threonine tyrosine kinase (TTK) in papillary thyroid cancer (PTC). TTK expression in PTC and normal groups were compared using TCGA data and in vitro experiments. The prognostic value of TTK and its possible role in PTC dedifferentiation was evaluated. Next, TTK involvement in PTC occurrence and progression was analyzed via in vitro experiments. Subsequently, analyses of enrichment and immune cell infiltration were conducted to reveal the possible mechanism. Finally, we predicted the target miRNAs followed by performing a luciferase reporter experiment. TTK upregulation was observed in PTC, and its elevated level was significantly related to an unfavorable prognosis (P < 0.05). Interestingly, TTK negatively correlated with thyroid differentiation score (TDS), and patients with higher TDS showed longer survival (all P < 0.05). PTC cell growth, migration, and invasion were inhibited upon TTK knockdown. Besides, TTK was involved in metabolic processes and regulated cell adhesion molecules pathway. Its overexpression was positively associated with immune cell infiltrates (P < 0.05). Moreover, miR-582-5p was an upstream target of TTK. TTK serves as a potential biomarker for tumorigenesis and prognosis in PTC, especially for those that may differentiate into more aggressive thyroid cancers.

The expression of two immunosuppressive SIGLEC family molecules in papillary thyroid cancer and their effect on prognosis.

The thyroid cancer (THCA) subtype that occurs more frequently is papillary thyroid cancer (PTC). Despite a favorable postoperative outcome, traditional antitumor therapy does not offer ideal results for patients with metastasis, relapse, and radioiodine resistance. Recent studies demonstrated the remarkable effects of immune checkpoint inhibitors on solid tumors, of which the immunoglobulin superfamily member SIGLEC10 and SIGLEC15 act as novel immunotherapy targets for tumors. Nevertheless, their role in PTC prognosis is still indefinite. Immunohistochemistry was utilized to examine the expression of SIGLEC10 and SIGLEC15 in 244 PTC tissue specimens. Then the expression correlation between the two was analyzed in normal tissues (NT), tumor cells (TC), and tumor stroma (TS), respectively. Subsequently, the retrospective data on patients with PTC were collected to examine whether the two immunosuppressive SIGLEC family members could affect their prognosis. We confirmed that TC expressed higher levels of SIGLEC10 than NT. However, SIGLEC10 was down-regulated in TS and predicted poor outcomes. Meanwhile, down-regulation of SIGLEC15 expression was observed in both TC and TS, indicating a favorable prognosis. PTC patients with both SIGLEC10-SIGLEC15+ expression in TC and TS had a significantly higher recurrence risk. The expression of SIGLEC10 in TS and SIGLEC15 in TC or TS was an independent predictor of PFS, and a positive correlation was shown between SIGLEC10 and SIGLEC15 expression in TS. Therefore, our results indicate that SIGLEC10 and SIGLEC15 may be applied as significant prognostic markers for PTC and attractive targets for THCA immunotherapy.

Bioinformatics analysis of the prognostic and clinical value of senescence-related gene signature in papillary thyroid cancer.

Cellular senescence can both inhibit and promote the occurrence of tumors, so how to apply cellular senescence therapy is of great importance. However, it is worth to be analyzed from multiple perspectives by researchers, especially for tumors with a high incidence like papillary thyroid cancer (PTC). We obtained senescence-related differentially expressed genes (SRGs) from The Cancer Genome Atlas (TCGA) and gene expression omnibus database. Enrichment analysis of SRGs was performed via gene ontology and Kyoto Encyclopedia of Genes and Genomes. Prognostic model was constructed by univariate and multivariate Cox regression analysis. Evaluation of clinical value was analyzed via Receiver operating characteristic curve, Kaplan-Meier curve and Cox regression. Immune infiltrates were investigated through ESTIMATE and single-sample gene set enrichment analysis. Immunohistochemical images were obtained from The Human Protein Atlas. Twenty-seven SRGs from TCGA cohort and gene expression omnibus datasets were found. These genes are mainly concentrated in senescence-related terms and pathways, including "DNA damage response, signal transduction by p53 class mediator," "signal transduction in response to DNA damage," "p53 signaling pathway" and "Endocrine resistance." Based on SRGs, prognostic model was constructed by E2F transcription factor 1, snail family transcriptional repressor 1 and phospholipase A2 receptor 1. PTC patients were divided into a low-risk group and a high-risk group according to the median value (cutoff point = 0.969) of risk score in TCGA cohort. The diagnostic efficiency of this model is good (area under curve = 0.803, 0.809, and 0.877 at 1, 2, and 3 years in TCGA; area under curve = 0.964, 0.813 in GPL570 and GPL96), particularly advanced grade, state and tumor mutation burden, such as Stage III - IV, T3 - 4, H-tumor mutation burden. Furthermore, High-risk group was significantly associated with poor prognosis and more immune infiltration. Our prognostic model has a good diagnostic and prognostic efficacy, and there is a certain clinical application value. In addition, we provide the first new insight into the genesis, diagnosis, prognosis and treatment of PTC based on senescence-related genes.

Causal inference between aggressive extrathyroidal extension and survival in papillary thyroid cancer: a propensity score matching and weighting analysis.

Extrathyroidal extension is a major risk factor for poor prognosis in papillary thyroid cancer. However, the effect of different degrees of extrathyroidal extension on prognosis remains controversial. We performed a retrospective study to elucidate how the extent of extrathyroidal extension in papillary thyroid cancer affected the clinical prognosis of patients and its covariates. The study included 108,426 patients with papillary thyroid cancer. We categorized the extent of extension into none, capsule, strap muscles, and other organs. Three causal inference methods for retrospective studies, namely, inverse probability of treatment weighting, standardized mortality ratio weighting, and propensity score matching analysis, were used to minimize potential selection bias. Kaplan-Meier analysis and univariate Cox regression analyses were applied to analyze the precise effect of ETE on survival in papillary thyroid cancer patients. In the Kaplan-Meier survival analysis, only extrathyroidal extension into or beyond the strap muscles was statistically significant for both overall survival (OS) and thyroid cancer-specific survival (TCSS). In univariate Cox regression analyses before and after matching or weighting based on causal inference, extrathyroidal extension into soft tissues or other organs is a high-risk factor for both overall survival and thyroid cancer-specific survival. Sensitivity analysis revealed that lower overall survival was observed in patients with older age (≥55) and larger tumor size (>2cm) of papillary thyroid cancer with extrathyroidal extension into or beyond the strap muscles. Our study indicates that extrathyroidal extension into soft tissues or other organs is a high-risk factor in all papillary thyroid cancer. Even though invasion into the strap muscles did not seem to be a marker for poor prognosis, it still impaired the overall survival of patients with older age (≥55 years old) or larger tumor size (>2cm). Further investigation is needed to confirm our results and to clarify further risk factors independent of extrathyroidal extension.

Differential microRNA expression for diagnosis and prognosis of papillary thyroid cancer.

Papillary thyroid cancer accounts for 85% of thyroid cancer. The diagnosis is based on ultrasound methods and tumor biopsies (FNA). In recent years, research has revealed the importance of miRNAs, non-coding RNA molecules that regulate gene expression and are involved in many diseases. The present mini review describes upregulated and downregulated miRNAs expression in papillary thyroid cancer patient samples (tissue, serum, plasma) and the genes regulated by these non-coding molecules. In addition, a bibliographic search was performed to identify the expression of miRNAs that are common in tumor tissue and blood. The miRNAs miR-146b, miR-221-3p, miRNA 222, miR-21, miR-296-5p, and miR-145 are common in both tissue and bloodstream of PTC patient samples. Furthermore, these miRNAs regulate genes involved in biological processes such as cell differentiation, proliferation, migration, invasion, and apoptosis. In conclusion, miRNAs could potentially become valuable biomarkers, which could help in the early diagnosis and prognosis of papillary thyroid cancer.

Papillary Thyroid Carcinoma: A Narrative Review on the Most Important Genetic and Epigenetic Alterations

Abstract: Papillary Thyroid Carcinoma (PTC) is the most common subtype of thyroid cancer that is the most prevalent one in the endocrine system. According to worldwide reports, its prevalence rate has been increasing in recent decades. The Discovery of DNA sequencing methods and molecular diagnostic techniques provides an insight into the understanding of PTC molecular biology and as well as in thyroidology, which opens a new perspective in finding molecular markers. Aligning cytological diagnostic methods with molecular behavior studies creates promising tools for better decision-making strategies for preoperative conditions to distinguish between benign from malignant thyroid nodules in challenging cases and limit unnecessary surgeries. Extensive studies have been performed on identifying the genes involved in PTC development and their prognosis. Currently, clinical and pathological features of the tumour (such as size, extrathyroid and lymph node invasion, and capsular invasion) are used to predict the prognosis of papillary thyroid cancer. In this review, we tried to summarize fundamental signaling pathways affecting PTC and the most important genetic alterations, including point mutations in proto-oncogenes and chromosomal rearrangements, as well as up/down-regulation of certain micro RNAs (miRNA) as an epigenetic change. Briefly, some of the most commonly altered genes in PTC are BRAF, RAS, RET, PAX8, PPARγ, and miRNAs like mir-146b, mir-221, mir-222, and mir-181b.

Identification and validation of eight estrogen-related genes for predicting prognosis of papillary thyroid cancer

Papillary thyroid cancer (PTC) is one of the most common malignant tumors in female, and estrogen can affect its progression. However, the targets and mechanisms of estrogen action in PTC remain unclear. Therefore, this study focuses on the relationship between estrogen-related genes (ERGs) expression and prognosis in PTC, particularly neuropeptide U (NMU), and its important role in tumor progression. Based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, differentially expressed genes (DEGs) predominantly enriched in ERGs were identified between PTC and normal tissue. Then, we identified ERGs that contributed most to PTC prognosis, including Transducer of ERBB2 1 (TOB1), trefoil factor 1 (TFF1), phospholipase A and acyltransferase 3 (PLAAT3), NMU, kinesin family member 20A (KIF20A), DNA topoisomerase II alpha (TOP2A), tetraspanin 13 (TSPAN13), and carboxypeptidase E (CPE). In addition, we confirmed that NMU was highly expressed in PTC and explored the effect of NMU on PTC cells proliferation in vitro and in vivo. The results showed that the proliferative capacity of PTC cells was significantly reduced with NMU knockdown. Moreover, the phosphorylation levels of the Kirsten rat sarcoma virus (KRAS) signaling pathway were significantly lower with NMU knockdown. These results suggest that ERGs, especially NMU, may be novel prognostic indicators in PTC.

A new molecular subclassification and in silico predictions for diagnosis and prognosis of papillary thyroid cancer by alternative splicing profile.

Introduction: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. However, different PTC variants reveal high heterogeneity at histological, cytological, molecular and clinicopathological levels, which complicates the precise diagnosis and management of PTC. Alternative splicing (AS) has been reported to be potential cancer biomarkers and therapeutic targets. Method: Here, we aim to find a more sophisticated molecular subclassification and characterization for PTC by integrating AS profiling. Based on six differentially expressed alternative splicing (DEAS) events, a new molecular subclassification was proposed to reclassify PTC into three new groups named as Cluster0, Cluster1 and Cluster2 respectively. Results: An in silico prediction was performed for accurate recognition of new groups with the average accuracy of 91.2%. Moreover, series of analyses were implemented to explore the differences of clinicopathology, molecular and immune characteristics across them. It suggests that there are remarkable differences among them, but Cluster2 was characterized by poor prognosis, higher immune heterogeneity and more sensitive to anti-PD1 therapy. The splicing correlation networks proved the complicated regulation relationships between AS events and splicing factors (SFs). An independent prognostic indicator for PTC overall survival (OS) was established. Finally, three compounds (orantinib, tyrphostin-AG-1295 and AG-370) were discovered to be the potential therapeutic agents. Discussion: Overall, the six DEAS events are not only potential biomarkers for precise diagnosis of PTC, but also the probable prognostic predictors. This research would be expected to highlight the effect of AS events on PTC characterization and also provide new insights into refining precise subclassification and improving medical therapy for PTC patients.

HIF1A overexpression predicts the high lymph node metastasis risk and indicates a poor prognosis in papillary thyroid cancer

ObjectiveTo investigate the value of Hypoxia-inducible factor 1 A (HIF1A) in predicting lymph node metastasis (LNM) stage and clinical outcomes of papillary thyroid cancer (PTC) patients. Materials and methodsThe HIF1A gene expression analysis in PTC was performed by bioinformatics approaches followed by evaluating its protein level using immunohistochemistry analysis. The role of HIF1A in predicting the LNM stage was evaluated by logistic regression analysis, nomogram construction, and receiver operating characteristic (ROC) analysis. We performed survival analyses to determine its prognostic value. Enrichment analysis was conducted, and immune cell infiltration and stromal content were evaluated to examine the underlying mechanism of HIF1A in PTC. ResultsHIF1A transcription and protein levels were significantly high in PTC tissue (P < 0.05). Its overexpression predicted high LNM risk and unfavorable prognosis for PTC patients (P < 0.05). Cox regression analysis revealed HIF1A as an independent prognostic biomarker for the disease-free interval (DFI) (P < 0.01). In addition, HIF1A was positively related to tumor-suppressive immunity but was negatively correlated with anti-tumor immunity. HIF1A upregulation was also associated with increased stromal content. ConclusionsHIF1A overexpression is an independent predictor for worse DFI in PTC. The HIF1A expression may affect the prognosis of PTC patients through immune- and stroma-related pathways. Our study provides new insight into the role of HIF1A in PTC biology and clinical management.

Age-dependent changes in the prognostic advantage of papillary thyroid cancer in women: A SEER-based study.

Papillary thyroid cancer (PTC) is more prevalent in women, and women show a better prognosis than men; however, the factors contributing to this prognostic difference are confounding. Therefore, we aimed to investigate the effect of the interaction between sex and age on the prognosis of PTC. A total of 108,459 patients with PTC were retrospectively analysed, and Cox-regression models were used to assess differences in disease specific survival (DSS) by sex, with inverse probability of treatment weighting (IPTW) to control for between-group differences in prognosis by sex due to age change. Restricted cubic splines were used to analyse prognostic differences between sexes for papillary thyroid microcarcinoma (PTMC) and PTC. Multiple mediation analyses were used to assess the direct or indirect effect of sex on DSS. The DSS was higher for women than men (98.6% vs. 95.4%, χ2 = 458.57, p < .001). After IPTW adjustment, the DSS of women was better than that of men (HR = 0.67, 0.60-0.76). In the subgroup analysis, women had an advantage in DSS across most age intervals (crude HR = 0.166 [0.082-0.337], p < .001, IPTW-adjusted HR = 0.331 [0.161-0.681], p < .001). The difference between the two gradually narrowed with increasing age, and the prognosis of women was better than that of men in PTMC, while this advantage was not obvious in PTC. The overall PTC prognosis of women is better than that of men, but the prognostic advantage of women diminishes with age and tumour growth. These differences in prognosis may be due to some indirect factors caused by different sexes.

Tumor-Infiltrating Immune Cell Landscapes in the Lymph Node Metastasis of Papillary Thyroid Cancer.

Regional lymph node metastasis (LNM) increases the risk of distant metastasis in papillary thyroid cancer (PTC) patients. However, it remains unclear how tumor cells in PTC patients with LNM evade immune system surveillance and proceed to colonize distant organs. Here, we comprehensively characterize the tumor-infiltrating immune cell landscape in PTC with LNM. LNM-related genes include multiple important soluble mediators such as CXCL6, IL37, MMP10, and COL11A1, along with genes involved in areas such as extracellular matrix organization and TLR regulation by endogenous ligands. In PTC without LNM, the tumor infiltration of activated dendritic cells and M0 macrophages showed increases from normal cells, but with yet greater increases and correspondingly worse prognosis in PTC with LNM. Conversely, the tumor infiltration of activated NK cells and eosinophils was decreased in PTC without LNM, as compared to normal cells, and yet further decreased in PTC with LNM, with such decreases associated with poor prognosis. We further demonstrate that mutations of driver genes in tumor cells influence the infiltration of surrounding immune cells in the tumor microenvironment (TME). Particularly, patients carrying TG mutations tend to show increased filtration of M2 macrophages and activated NK cells in the TME, whereas patients carrying HRAS mutations tend to show reduced filtration of M0 macrophages and show enhanced filtration of activated dendritic cells in the TME. These findings increase our understanding of the mechanisms of regional lymph node metastasis in PTC and its associated tumor microenvironment, potentially facilitating the development of personalized treatment regimens to combat immunotherapy failure.

Identification of a four-miRNA signature predicts the prognosis of papillary thyroid cancer.

In recently diagnosed patients with thyroid cancer, papillary thyroid cancer (PTC), as the most common histological subtype, accounts for 90% of all cases. Although PTC is known as a relatively adolescent malignant disease, there still is a high possibility of recurrence in PTC patients with a poor prognosis. Therefore, new biomarkers are necessary to guide more effective stratification of PTC patients and personalize therapy to avoid overtreatment or inadequate treatment. Accumulating evidence demonstrates that microRNAs (miRNAs) have broad application prospects as diagnostic biomarkers in cancer. To explore novel markers consisting of miRNA-associated signatures for PTC prognostication. We obtained and analyzed the data of 497 PTC patients from The Cancer Genome Atlas. The patients were randomly assigned to either a training or testing cohort. We discovered 237 differentially expressed miRNAs in tumorous thyroid tissues compared with normal tissues, which contained 172 up-regulated and 65 down-regulated miRNAs. The evaluation of differently expressed miRNAs was conducted using our risk score model. We then successfully generated a four-miRNA potential prognostic signature [risk score = (-0.001 × hsa-miR-181a-2-3p) + (0.003 × hsa-miR-138-5p) + (-0.018 × hsa-miR-424-3p) + (0.284 × hsa-miR-612)], which reliably distinguished patients from high and low risk with a significant difference in the overall survival (P < 0.01) and was effective in predicting the five-year disease survival rate with the area under the receiver operating characteristic curve of 0.937 and 0.812 in the training and testing cohorts, respectively. Additionally, there was a trend indicated that high-risk patients had shorter relapse-free survival, although statistical significance was not reached (P = 0.082) in our sequencing cohort. Our results indicated a four-miRNA signature that has a robust predictive effect on the prognosis of PTC. Accordingly, we would recommend more radical therapy and closer follow-ups for high-risk groups.