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Background: Hashimoto's thyroiditis (HT) is a chronic autoimmune disease that poses a risk factor for papillary thyroid carcinoma (PTC). The present study aimed to identify the key genes shared by HT and PTC for advancing the current understanding of their shared pathogenesis and molecular mechanisms., Methods: HT- and PTC-related datasets (GSE138198 and GSE33630, respectively) were retrieved from the Gene Expression Omnibus (GEO) database. Genes significantly related to the PTC phenotype were identified using weighted gene co-expression network analysis (WGCNA). Differentially expressed genes (DEGs) were identified between PTC and healthy samples from GSE33630, and between HT and normal samples from GSE138198. Subsequently, functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Transcription factors and miRNAs regulating the common genes in PTC and HT were forecasted using the Harmonizome and miRWalk databases, respectively, and drugs targeting these genes were investigated using the Drug-Gene Interaction Database (DGIdb). The key genes in both GSE138198 and GSE33630 were further identified via Receiver Operating Characteristic (ROC) analysis. The expression of key genes was verified in external validation set and clinical samples using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC)., Results: In total, 690 and 1945 DEGs were associated with PTC and HT, respectively; of these, 56 were shared and exhibited excellent predictive accuracy in the GSE138198 and GSE33630 cohorts. Notably, four genes, Alcohol Dehydrogenase 1B ( ADH1B ), Active BCR-related ( ABR ), alpha-1 antitrypsin ( SERPINA1 ), and lysophosphatidic acid receptor 5 ( LPAR5 ) were recognized as key genes shared by HT and PTC. Subsequently, EGR1 was identified as a common transcription factor regulating ABR, SERPINA1 , and LPAR5 expression. These findings were confirmed using qRT-PCR and immunohistochemical analysis., Conclusion: Four ( ADH1B, ABR, SERPINA1 , and LPAR5 ) out of 56 common genes exhibited diagnostic potential in HT and PTC. Notably, this study, for the first time, defined the close relationship between ABR and HT/PTC progression. Overall, this study provides a basis for understanding the shared pathogenesis and underlying molecular mechanisms of HT and PTC, which might help improve patient diagnosis and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Yin, Wang, Li, Dong and Peng.)

Background: Thyroid cancer is rapidly increasing in incidence worldwide in the past several decades, same as the incidence of metabolic syndrome. We performed a system review and meta-analysis of the association between metabolic syndrome, its components and insulin resistance and thyroid cancer incidence., Methods: We searched several computer-assisted databases PUBMED, EMBASE and ISI Web of Science to identify studies published before 31st January 2018. Every study must report either risk estimates of thyroid cancer incidence with 95% confidence interval (CI) or related data can speculate. Two investigators independently identified eligible studies and extracted data. Evaluating the summaries of relative risk estimates use both fixed and random effects methods., Results: We found 42 articles met the inclusion criteria of this review. There is an increased risk for thyroid cancer for patients with insulin resistance (relative risk [RR] = 1.59, 95%confidence interval [CI] = 1.12-2.27, P = 0.01), dysglycemia (RR = 1.40, 95%CI = 1.15-1.70,P < 0.001), high BMI (RR = 1.35,95%CI = 1.23-1.48,P < 0.001) and hypertension(RR = 1.34,95%CI = 1.22-1.47, p < 0.001). However, patients with dyslipidemia, both total cholesterol (RR = 1.09, 95%CI = 0.98-1.21, P = 0.13) and triglyceride (RR = 1.01, 95%CI = 0.91-1.12, P = 0.82) was not associated with thyroid cancer., Conclusions: Our meta-analysis showed Insulin Resistance, dysglycemia, high BMI and hypertension significantly increased the thyroid cancer risk. These results may help identify people with high risk of thyroid cancer and change to healthy life style., (Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: It is widely accepted that maximal extrathyroidal extension (ETE) plays a vital role in the prognosis of papillary thyroid carcinoma (PTC). However, there is no consensus among researchers about the meaning of minimal ETE (mETE) in PTC. Herein, we conducted a systematic review and meta-analysis to examine the role of mETE in the prognosis of PTC., Methods: We searched PubMed, EMBASE, and Cochrane search trials databases in English to identify studies comparing data on disease recurrence in PTC patients with mETE and those with no ETE. To summarize the data related to mETE status, risk ratios and hazard ratios adjusted for potential confounders were used to assess the number of recurrence and time-dependent risks related to mETE status, respectively., Results: According to the inclusion criteria, a total of 7951 patients from 9 studies were included. The recurrence rate in patients with mETE is significantly higher when compared with those with no ETE (risk ratio = 1.70, 95% confidence interval: 1.26-2.28, I = 56%). According to the data summarized with hazard ratios, PTC patients with mETE showed a significantly increased risk of disease recurrence., Conclusion: mETE is a risk factor for poor prognosis in patients with PTC. Our innovative classification of ETE has its value in assessing the prognosis of PTC., Competing Interests: The authors have no conflicts of interest to disclose.

Background: The prognostic value of the telomerase reverse transcriptase (TERT) promoter mutation, resulting in poor clinical outcomes of papillary thyroid carcinoma (PTC), has been generally confirmed. To data, there is no high-level evidence approving the association of TERT promoter mutation and aggressive clinical behaviours in PTC. To systematically evaluate it, a systematic review and meta-analysis of the published literatures were carried out., Methods: We conducted a systematic search in PubMed, EMBASE, OVID and Web of Science databases for relevant studies. We selected all the studies that reported clinicopathological features of PTC patients with information available on TERT promoter mutation status. Individual study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, as were Mantel-Haenszel pooled odds ratios for the combined studies., Results: Eight eligible trials involved 2035 patients were included in the analysis. The average prevalence of the TERT promoter mutation was 10·32%. Compared with the wild-type TERT promoter gene, the TERT promoter mutation was associated with male gender, lymph node metastasis, extrathyroidal extension, distant metastasis, advanced TNM stage III/IV, poor clinical outcome (persistence or recurrence) and mortality. The associations were generally consistent across the different study populations., Conclusions: Thus, our findings from this large meta-analysis definitively demonstrate that TERT promoter mutation-positive PTC is more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the TERT promoter mutation is likely to be useful in assisting the risk stratification and management of PTC., (© 2016 John Wiley & Sons Ltd.)

Background: Some studies showed an association of coiled-coil domain-containing (CCDC) genes with cancers. Our previous limited data specifically suggested a possible pathogenic role of CCDC67 in papillary thyroid cancer (PTC), but this has not been firmly established. The present study was to further investigate and establish this role of CCDC67 in PTC., Results: The expression of CCDC67, both at mRNA and protein levels, was sharply down-regulated in PTC compared with normal thyroid tissues. Lower CCDC67 expression was significantly associated with aggressive tumor behaviors, such as advanced tumor stages and lymph node metastasis, as well as BRAF mutation. Introduced expression of CCDC67 in TPC-1 cells robustly inhibited cell proliferation, colony formation and migration, induced G1 phase cell cycle arrest, and increased cell apoptosis., Methods: Primary PTC tumors and matched normal thyroid tissues were obtained from 200 unselected patients at the initial surgery for detection of CCDC67 mRNA and protein by RT-PCR and Western blotting analyses, respectively. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. Clinicopathological data were retrospectively reviewed for correlation analyses. PTC cell line TPC-1 with stable transfection of CCDC67 was used to investigate the functions of CCDC67., Conclusions: This large study demonstrates down-regulation of CCDC67 in PTC, an inverse relationship between CCDC67 expression and PTC aggressiveness and BRAF mutation, and a robust inhibitory effect of CCDC67 on PTC cellular activities. These results are consistent with CCDC67 being a novel and impaired tumor suppressor gene in PTC, providing important prognostic and therapeutic implications for this cancer.

The expression of the Dickkopf homolog 3 (DKK3) gene is downregulated in some human cancers, suggesting a possible tumor suppressor role of this gene. The role and regulation of DKK3 in thyroid cancer have not been examined. In this study, we explored the relationship of promoter methylation with the inactivation of DKK3 and tumor behaviors in papillary thyroid carcinoma (PTC). We used methylation-specific PCR and RT-PCR to examine the promoter methylation and expression of DKK3 and tumor characteristics. We found mRNA expression of DKK3 in 44.9% of the PTC tissue samples vs 100% of the matched normal thyroid tissue samples (P<0.01). In contrast, an opposite distribution pattern of DKK3 gene methylation was observed; specifically, 38.8% of the PTC tissue samples vs 0% of the matched normal thyroid tissue samples harbored DKK3 methylation. An inverse correlation between the promoter methylation and mRNA expression of DKK3 in PTC tissue samples was also observed. Moreover, we also found an inverse correlation between DKK3 expression and some aggressive pathological characteristics of PTC, including high TNM stages and lymph node metastasis, but a positive correlation between DKK3 promoter hypermethylation and pathological aggressiveness of the tumor. Treatment of the PTC cell line TPC-1 with the demethylating agent 5-azaC reduced DKK3 promoter methylation and enhanced its expression, establishing functionally the impact of DKK3 methylation on its expression. Our data thus for the first time demonstrate that the DKK3 gene is a potential tumor suppressor gene in thyroid cancer and that aberrant promoter methylation is an important mechanism for its downregulation, which may play a role in the tumorigenesis and aggressiveness of PTC.

Objective: To elucidate the mechanisms undergoing the pathogenesis of PTC, this study try to find stage specific microRNAs (miRNAs) using microarray chip in stage I, II and III papillary thyroid carcinoma (PTC) tissues as well predict miRNAs binding target genes and their molecular functions., Methods: PTC specimens of stage I, II, and III and their paired adjacent non-tumor tissue (one patient for each stage) were collected. The expressions of miRNAs were examined using miRNA microarray chip. The most significant changed miRNAs from microarray were verified by using quantitative RT-PCR. The Potential miRNAs regulating target genes and their preliminary biological functions were forecasted with variety function prediction software., Results: Ten miRNAs exhibited sequential up regulation expression profiles and five miRNAs performed sequential down regulation throughout stage I to III (p<0.05). After normalization, Fifteen miRNAs showed significant different compared to adjacent non-tumor tissues (p<0.05). Among of them, the most significant up regulation and down regulation miRNAs were miR-146b-5p and miR-335, respectively. Both of them were verified with qRT-PCR. 34 target genes for miR-146-5p and 36 target genes for miR-335 was predicted., Conclusion: MicroRNA profile assay successfully detected a branch of differential expression miRNAs between PTC and normal tissue. Some of them also showed stage specific. Biological function analysis showed that target genes were involved in five aspects including cell proliferation, differentiation, apoptosis, cycle, and signaling transduction pathway, suggesting the regulatory role of abnormal expression of critical miRNAs in the pathogenesis of PTC.

Objective: To explore the relationship between methylation status of XAF1 (X-linked inhibitor of apoptosis protein associated factor-1) gene promoter and its protein expression in papillary thyroid carcinoma (PTC)., Methods: Methylation-specific polymerase chain reaction (MSP) and immunohistochemical substance P (SP) technique were used to detect the methylation status of XAF1 gene promoter and its protein expression in 70 PTC cases and their matched adjacent non-cancerous epithelium (NCE)., Results: In NCE, there was no promoter methylation of XAF1 gene while the rate was 35.7% (25/70) in PTC (χ(2) = 27.206, P < 0.01). And it was correlated with tumor TNM stage, pathological grade and lymph node metastasis (P < 0.05). The positive rates of XAF1 protein expression in NCE and PTC were 100% (70/70) and 55.7% (39/70) respectively. And there was significant difference (χ(2) = 36.458, P < 0.01). In PTC, the positive rates of XAF1 protein expression in Grades I and II were 67.5% (27/40) and 40.0% (12/30) respectively. And they were 35.7% (10/28) and 69.0% (29/42) in the lymph node metastasis and non-metastasis groups respectively. And there were significant differences between two groups (P < 0.05). Futhermore, there was distinct correlation between methylation of XAF1 gene promoter and its protein expression (χ(2) = 8.864, P < 0.01)., Conclusion: Methylation of promoter may be one of the important inactivating factors of XAF1 gene. And it plays an important role in the carcinogenesis and progression of PTC.

Objective: To explore the mRNA and protein expressions of Runx3 gene in papillary thyroid carcinoma (PTC)., Methods: Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the Runx3 mRNA and protein levels in 67 human PTC specimens and their matched adjacent non-cancerous epithelium (NCE)., Results: The relative expression value of Runx3 mRNA was 0.31 ± 0.07 in PTC versus 0.92 ± 0.08 in NCE (t = 38.251, P < 0.05). In PTC, it was correlated with the tumor pathological grade and lymph node metastasis (χ(2) = 5.511, 6.492, P < 0.05). The integral optical density value of Runx3 protein confirmed was 1012 ± 221 in PTC versus 1993 ± 199 in NCE (t = 18.413, P < 0.05). In PTC, it was correlated with the tumor TNM stage, pathological grade and lymph node metastasis (χ(2) = 5.550, 9.678, 5.070, P < 0.05). Furthermore there was a distinct correlation between the mRNA and protein expressions of Runx3 gene (χ(2) = 42.699, P < 0.05)., Conclusion: The mRNA and protein expressions of Runx3 gene in PTC were lower than those in NCE. A lower expression of Runx3 gene may play an important role in the carcinogenesis and progression of PTC.

Objective: To study the relationship between status of methylation of human runt-related transcription factor 3 (RUNX3) gene promoter in papillary thyroid carcinoma (PTC)., Methods: Methylation-specific PCR and immunohistochemical SP technique were used to detect the methylation of RUNX3 gene promoter and expression of its protein in 56 cases of PTC and their matched adjacent non-carcinous epithelium (NCE)., Results: In NCE, there was no methylation of RUNX3 gene promoter, while in PTC the methylation rate was 35.7%(20/56), which was related to the tumor TNM stage, pathological grade and lymph node metastasis (P < 0.05). The positive rates of RUNX3 protein expression in NCE and PTC were 100.0% and 60.7%, respectively, with a significant difference (χ(2) = 27.378, P < 0.05). In PTC, the positive rates of RUNX3 protein expression in gradeI and grade II were 70.0% and 37.5%, respectively (P < 0.05); the rates were 46.7% and 76.9% in lymph node metastasis group and no metastasis group, respectively (P < 0.05). Moreover, there was a distinct correlation between methylation of RUNX3 gene promoter and expression of its protein (χ(2) = 21.62, P < 0.01)., Conclusions: Methylation of promoter might be one of the important factors of inactivation of RUNX3 gene, and might play an important role in carcinogenesis and progression of PTC.

Objective: To study the expressions of Piwil2 protein and mRNA in papillary thyroid carcinoma (PTC) and the relationship between Piwil2 and the invasion and metastasis of PTC., Methods: Immunohistochemistry and in situ hybridization were used to detect the expression of Piwil2 protein and mRNA in 60 cases of PTC with the matched adjacent non-cancerous epithelium (NCE)., Results: The positive rates of Piwil2 protein expression in PTC and NCE were 88.3% (53/60) and 10.0% (6/60) respectively, with significant difference (χ² = 73.654, P < 0.01). The positive rates of Piwil2 mRNA expression in PTC and NCE were 85.0% (51/60) and 6.7% (4/60) respectively, also with significant difference (χ(2) = 74.148, P < 0.01). Up-regulated expressions of Piwil2 protein and mRNA were related to the invasion and metastasis of PTC (P < 0.05)., Conclusions: Piwil2 may play a role in the invasion and metastasis of PTC.

The fragile histidine triad (FHIT) gene encompasses the most common human fragile site, FRA3B at 3p14.2, a region that is involved in homozygous deletions in a variety of human tumors. FHIT is considered to be a tumor suppressor gene that is frequently inactivated in various types of cancer. To study the role of the FHIT gene in thyroid tumorigenesis, we looked for homozygous deletions or mutations of exons 5 and 8 of the FHIT gene in 65 cases of differentiated thyroid carcinoma (DTC) and their matched non-cancerous epithelium (NCE), using exon-specific PCR amplification and PCR single strand conformation polymorphism (PCR-SSCP) techniques. In DTC, the incidence of homozygous deletion of exon 5 was 30.8% (20/65), and it was associated with tumor metastasis to lymph nodes (p <0.05). The incidence of homozygous deletion of exon 8 was 29.2% (19/65), and it was associated with the tumor pathological grade, TNM stage, and lymph node metastasis (p <0.05). There was strong correlation between homozygous deletions of exon 5 and exon 8 (p <0.01). No point mutations were observed in either exon 5 or exon 8. These findings suggest that: (a) exons 5 and 8 of FHIT are key target regions of deletion, (b) homozygous deletions of exon 5 and exon 8 may be good biomarkers for the biological behavior of DTC, and (c) point mutation of these exons may not be involved in the inactivation of the FHIT gene in DTC.

The role of aberrant methylation of fragile histidine triad (FHIT) promoters in the differentiated thyroid carcinoma (DTC) is not yet clear. Therefore, we investigated the association of the status of FHIT promoter methylation and FHIT protein expression with the clinicopathological progression of DTC, using PCR-based methylation assay and immunohistochemical technique. While no FHIT gene promoter methylation was observed in the matched non-cancerous epithelium (NCE) specimens, 24.6% of DTC samples demonstrated methylation in the FHIT promoter region. The protein expression of FHIT in NCE and DTC was 100.0% and 41.5% (P<0.01), respectively. There was a negative correlation between promoter methylation and protein expression of FHIT gene (P<0.05). Additionally, the methylation status appeared to be significantly associated with the pathological grade, tumor TNM stage, and lymph node metastasis (P<0.05), and FHIT proteins were weakly expressed in only about 20% of DTC with grade II pathological changes, TNM stage III/IV, or lymph node metastasis. Finally, the gender and tumor classification but not age marginally affected the promoter methylation and protein expression of FHIT. Our results suggest that methylation of the promoter region may play a key role in inactivation of FHIT - possibly leading to subsequent carcinogenesis and progression of DTC.