Pathogenesis Of Papillary Thyroid Cancer Research Articles

Molecular Network-Based Identification of Circular RNA-Associated ceRNA Network in Papillary Thyroid Cancer.

Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. Nevertheless, their function and underlying mechanisms in papillary thyroid cancer (PTC) remains largely unknown. This study aimed to describe the regulatory mechanisms in PTC. The expression profile of circRNA was download from the Gene Expression Omnibus (GEO) database. The mRNA and miRNA data of PTC was downloaded from The Cancer Genome Atlas (TCGA) database. The circRNA-miRNA-mRNA network by Cytoscape. The interactions between proteins were analyzed using the STRING database and hubgenes were identified using MCODE plugin. Then, we conducted a circRNA-miRNA-hubgenes regulatory module. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis were conducted using R packages "Clusterprofile". We identified 14 differential expression circRNAs (DEcircRNA), 3106 differential expression mRNAs (DEmRNA), 142 differential expression miRNAs (DEmiRNA) and in PTC. Twelve circRNAs, 33 miRNAs, and 356 mRNAs were identified to construct the ceRNA network of PTC. PPI network and module analysis identified 5 hubgenes. Then, a circRNA-miRNA-hubgene subnetwork was constructed based on the 2 DEcircRNAs, 3 DEmiRNAs, and 4 DEmRNAs. GO and KEGG pathway analysis indicated DEmRNAs might be associated with PTC onset and progression. These ceRNAs are critical in the pathogenesis of PTC and may serve as future therapeutic biomarkers.

Polymorphisms of the Highly Expressed IL-6 Gene in the Papillary Thyroid Cancer Susceptibility Among Chinese.

Papillary thyroid cancer (PTC) is the cardinal histologic type of thyroid cancer, which is the most prevalent kind of endocrine malignancy. The expression of IL-6 is found higher in thyroid carcinoma (THCA) samples than paired normal tissues based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue expression (GTEx) database. In this study, we aimed to investigate the association between interleukin-6 (IL-6) polymorphisms and the PTC risk. A case-control study was designed using the following data: 241 PTC patients and 463 healthy controls. Five single nucleotide polymorphisms (SNPs) in IL-6 were selected and genotyped using Agena MassARRAY technology. Our results revealed that SNP rs1800796 was associated with an increased PTC risk in co-dominant model (p = 0.042) and dominant model (p = 0.027). Rs1524107 was also a risk factor for PTC susceptibility in co-dominant model (p = 0.003), dominant model (p = 0.002) and log-additive model (p = 0.044). Moreover, rs2066992 significantly increased the PTC risk in co-dominant model and dominant model (p = 0.011, p = 0.009, respectively). Additionally, rs2069837 variant elevated the PTC risk based on dominant model (p = 0.041). In silico analysis, GTEx results for rs1800796, rs1524107 and rs2066992 variants are known to be associated with IL-6 gene expression. Using HaploReg, we found rs1800796, rs1524107 and rs2066992 in LD with functional importance. Our study indicates that IL-6 variants may be a risk factor involved in the pathogenesis and development of PTC.

Systems Biology Approaches to Investigate Genetic and Epigenetic Molecular Progression Mechanisms for Identifying Gene Expression Signatures in Papillary Thyroid Cancer.

Thyroid cancer is the most common endocrine cancer. Particularly, papillary thyroid cancer (PTC) accounts for the highest proportion of thyroid cancer. Up to now, there are few researches discussing the pathogenesis and progression mechanisms of PTC from the viewpoint of systems biology approaches. In this study, first we constructed the candidate genetic and epigenetic network (GEN) consisting of candidate protein–protein interaction network (PPIN) and candidate gene regulatory network (GRN) by big database mining. Secondly, system identification and system order detection methods were applied to prune candidate GEN via next-generation sequencing (NGS) and DNA methylation profiles to obtain the real GEN. After that, we extracted core GENs from real GENs by the principal network projection (PNP) method. To investigate the pathogenic and progression mechanisms in each stage of PTC, core GEN was denoted in respect of KEGG pathways. Finally, by comparing two successive core signaling pathways of PTC, we not only shed light on the causes of PTC progression, but also identified essential biomarkers with specific gene expression signature. Moreover, based on the identified gene expression signature, we suggested potential candidate drugs to prevent the progression of PTC with querying Connectivity Map (CMap).

Effect of MALAT1 Polymorphisms on Papillary Thyroid Cancer in a Chinese Population.

Background: Long noncoding RNA MALAT1 has been previously reported in the carcinogenesis of several tumors, and its potential functional polymorphisms have also been investigated in various diseases. However, the relationship between these polymorphisms and the susceptibility of thyroid cancer has still been largely unknown. In the present study, we aimed to explore the association between MALAT1 polymorphisms and thyroid cancer (TC) susceptibility, as well as potential biological function in TC.Methods: We conducted a case-control study with 1134 papillary thyroid cancer (PTC) patients and 1228 controls to evaluate the potential correlation between MALAT1 genetic variations (single nucleotide polymorphism, SNP) and the risk of PTC. More detailed molecular mechanisms were explored by luciferase assay, cell counting kit-8 (CCK-8), and flow cytometry.Results: MALAT1 SNP rs619586 was identified as a significantly protective factor of PTC susceptibility (P = 0.017, OR= 0.76, 95%CI = 0.60-0.95). Further functional experiments of rs619586 indicated that G allele of rs619586 could significantly decrease MALAT1expression, reduce PTC proliferation, and directly increase PTC apoptosis.Conclusions: Our findings suggested that MALAT1 SNP rs619586 could serve as a potential indicator for PTC susceptibility and pathogenesis.

A novel lncRNA-miRNA-mRNA network analysis identified the hub lncRNA RP11-159F24.1 in the pathogenesis of papillary thyroid cancer

Papillary thyroid cancer (PTC) is one of the most common cancers worldwide, and its carcinogenesis is influenced by a complex network of gene interactions. In this study, the microarray expression profile was re‐annotated into a lncRNA‐mRNA biphasic profile. LncRNA‐mRNA interactions were confirmed by established miRNA‐RNA data and hypergeometric test. Then, a PTC‐related lncRNA‐miRNA‐mRNA network (PTCRN) was constructed by integrating differentially expressed genes with the RNA‐RNA networks. The new network consisted of 21 lncRNAs, 241 mRNAs and 803 edges. To prioritize PTC‐related genes, we performed topological analysis and random walk with restart (PWR) algorithm analysis of PTCRN. Both analyses identified lncRNA RP11‐159F24.1 as a hub node in the network, which could interact with 47 mRNAs by sponging miR‐485. In functional enrichment analysis, these interacting mRNAs were associated with the pathways in cancer. In validation, RP11‐159F24.1 (up‐regulated; P = 0.0013) showed an opposite expression pattern with its target miR‐485 (down‐regulated; P = 0.0013) in PTC, indicating that the RP11‐159F24.1/miR‐485/mRNAs axis might play an important role in the development of PTC. In conclusion, this study has constructed a PTC‐related lncRNA‐miRNA‐mRNA network and identified the hub lncRNA RP11‐159F24.1 in the tumorigenesis, which provided novel insights to explore the underlying mechanism of PTC.

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway.

MicroRNAs (miRNAs/miRs) are widely dysregulated in papillary thyroid cancer (PTC). Dysregulated miRNAs, together with their target genes, comprise a complex network that has been implicated in the regulation of PTC pathogenesis. Further knowledge of the functional roles of aberrantly expressed miRNAs in PTC, and the underlying molecular mechanisms, may assist in the identification of novel therapeutic targets. miR‑766 has been well studied in human cancer; however, the expression status, specific roles and regulatory mechanisms of miR‑766 in PTC remain unclear. The present study aimed to detect miR‑766 expression in PTC tissues and cell lines, to explore the biological roles of miR‑766 in the malignant biological behaviors of PTC cells, and to determine the underlying mechanism of action of miR‑766 in PTC cells. The results revealed that miR‑766 was downregulated in PTC tissues and cell lines, and its downregulation was strongly associated with TNM stage and lymph node metastasis. Overexpression of miR‑766 inhibited PTC cell proliferation, colony formation, migration and invasion, promoted cell apoptosis and reduced tumor growth invivo. Mechanistically, insulin receptor substrate2 (IRS2) was identified as a direct target of miR‑766 in PTC cells. IRS2 was upregulated in PTC tissues, and this was inversely correlated with miR‑766 expression. Inhibition of IRS2 simulated the tumor suppressor activity of miR‑766 in PTC cells. Restoration of IRS2 expression negated the tumor‑suppressing effects of miR‑766 overexpression on PTC cells. Notably, miR‑766 directly targeted IRS2 to inhibit activation of the phosphoinositide3‑kinase (PI3K)/protein kinaseB (Akt) pathway in PTC cells invitro and invivo. Overall, these findings indicated that miR‑766 may inhibit the malignant biological behaviors of PTC cells by directly targeting IRS2 and regulating the PI3K/Akt pathway, thus suggesting that this miRNA may be a promising therapeutic target for PTC.

Expression and Function of Long Noncoding RNA NONHSAT129183 in Papillary Thyroid Cancer.

The aberrant expression of long noncoding RNAs (lncRNAs) is implicated in cancer development and progression. This study was aimed to investigate the expression and clinical significance of lncRNA NONHSAT129183 in papillary thyroid cancer (PTC), and to explore its roles in PTC cell proliferation, migration, and invasion. Our results demonstrate that lncRNA NONHSAT129183 is upregulated in human PTC tissues when compared with that in adjacent noncancerous thyroid tissue. Moreover, its expression is correlated with tumor size, lymph node metastasis, and TNM stage in PTC patients. lncRNA NONHSAT129183 silencing also significantly suppressed cell proliferation, migration, and invasion in PTC cell lines. In conclusion, our results suggest that lncRNA NONHSAT129183 plays a critical role in the regulation of PTC cell proliferation, migration, and invasion, providing new insights into PTC pathogenesis.

Retracted: MicroRNA‐150‐5p affects cell proliferation, apoptosis, and EMT by regulation of the BRAFV600E mutation in papillary thyroid cancer cells

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Studies have confirmed an association between microRNA (miRNA) and the BRAFV600E mutation in various cellular biological processes of PTC. This study aimed to clarify the potential relationship between miR-150-5p and the BRAFV600E mutation in PTC. Human PTC cell lines B-CPAP and TPC-1 were transfected with the miR-150-5p mimic, an inhibitor, and the corresponding controls. Then, cell proliferation, viability, and apoptosis were detected by bromodeoxyuridine, trypan blue exclusion, and flow cytometry assays. The expressions of the main factors of cell cycle, epithelial mesenchymal transition (EMT), and DNA mismatch repair were examined by Western blot analysis and a real-time quantitative polymerase chain reaction. Additionally, pc-BRAFV600E was transfected into B-CPAP and TPC-1 cells to determine the relationship between miR-150-5p and BRAFV600E . In addition, the methyl ethyl ketone (MEK)/extracellular signal-regulated kinase (ERK) signal pathway was examined using Western blot analysis. Overexpression of miR-150-5p promoted cell proliferation and viability, inhibited apoptosis, and upregulated cell cycle factor expressions at 50 passages of B-CPAP and TPC-1 cells after transfection. Overexpression of miR-150-5p led to an obvious decrease in E-cadherin expression, but enhanced N-cadherin, Slug and Vimentin, ZEB1, and Snail expression. Moreover, overexpression of miR-150-5p markedly suppressed POLD3, MSH2, and MSH3 expression. Furthermore, BRAFV600E overexpression increased the expression level of miR-150-5p in TPC cells, and overexpression of telomerase reverse transcriptase further enhanced the promoting effect of BRAFV600E on miR-150-5p expression in B-CPAP and TPC-1 cells. Finally, BRAFV600E overexpression activated the MEK/ERK signal pathway in B-CPAP and TPC-1 cells. These data indicated that miR-150-5p promoted cell proliferation, suppressed apoptosis, and accelerated the EMT process by regulation of the BRAFV600E mutation. Our findings will help elucidate the pathogenesis of PTC and identify biomarkers.

Identification of potential functional genes in papillary thyroid cancer by co-expression network analysis.

Interactions between multiple genes are involved in the development of complex diseases. However, there are few analyses of gene interactions associated with papillary thyroid cancer (PTC). Weighted gene co-expression network analysis (WGCNA) is a novel and powerful method that detects gene interactions according to their co-expression similarities. In the present study, WGCNA was performed in order to identify functional genes associated with PTC using R package. First, differential gene expression analysis was conducted in order to identify the differentially expressed genes (DEGs) between PTC and normal samples. Subsequently, co-expression networks of the DEGs were constructed for the two sample groups, respectively. The two networks were compared in order to identify a poorly preserved module. Concentrating on the significant module, validation analysis was performed to confirm the identified genes and combined functional enrichment analysis was conducted in order to identify more functional associations of these genes with PTC. As a result, 1062 DEGs were identified for network construction. A brown module containing 118 highly related genes was selected as it exhibited the lowest module preservation. After validation analysis, 61 genes in the module were confirmed to be associated with PTC. Following the enrichment analysis, two PTC-related pathways were identified: Wnt signal pathway and transcriptional misregulation in cancer. LRP4, KLK7, PRICKLE1, ETV4 and ETV5 were predicted to be candidate genes regulating the pathogenesis of PTC. These results provide novel insights into the etiology of PTC and the identification of potential functional genes.

MicroRNA-146b: A Novel Biomarker and Therapeutic Target for Human Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is the most common tumor subtype of thyroid cancer. However, not all PTCs are responsive to current surgical and radioiodine treatment. The well-established clinical prognostic factors include tumor size, lymph node/distal metastasis, and extrathyroidal invasion. The RET/PTC-RAS-BRAF linear molecular signaling cascade is known to mediate PTC pathogenesis. However, whether presence of BRAF mutation, the most common genetic alteration in PTC, can affect PTC behavior and prognosis is controversial. MicroRNAs (miRNAs) have been labeled as promising molecular prognostic markers in several tumor types. Our recent studies demonstrated that microRNA-146b (miR-146b) deregulation is associated with PTC aggressiveness and prognosis. Here we summarize the current knowledge related to the functional roles, regulated target genes, and clinical applications of miR-146b in PTC and discuss how these studies provide insights into the key role of miR-146b as an oncogenic regulator promoting cellular transformation as well as a prognosis marker for tumor recurrence in PTC. In conjunction with the current perspectives on miRNAs in a wide variety of human cancers, this review will hopefully translate these updated findings on miR-146b into more comprehensive diagnostic or prognostic information regarding treatment in PTC patients before surgical intervention and follow up strategies.

Significance of expression of suppressor of cytokine signaling proteins: Suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, and suppressor of cytokine signaling-3 in papillary thyroid cancer.

Uncontrolled cytokine signal transduction largely associated with oncogene activation, can have disastrous biological consequences. The suppressor of cytokine signaling (SOCS) proteins represent one of the mechanisms by which this rampant signaling can be dissipated. Thus, we aimed to study the expression of SOCS-1, SOCS-2, and SOCS-3 in patients having benign thyroid disease and papillary thyroid cancer. SOCS protein expression was studied in 45 patients with benign thyroid disease and in 83 papillary thyroid cancer patients by immunohistochemistry and their association with clinicopathological characteristics and overall survival in cancer patients were analyzed using SPSS software. Expressions of SOCS proteins were significantly higher in papillary thyroid cancer than in patients having benign disease. SOCS-1 expression was predominantly higher in males (P = 0.004), unilateral tumors (P = 0.030), and noninflammatory conditions (P = 0.028). SOCS-1 expression was also able to predict poor overall survival in subgroup of papillary thyroid cancer patients having larger tumor size (P = 0.013) and advanced stage disease (P = 0.033). Expression of SOCS-2 significantly correlated with tumor size (P = 0.017), extrathyroidal extension (P = 0.000), residual disease (P = 0.043), and treatment (P = 0.007), while preponderance of SOCS-3 expression was observed in males (P = 0.030) and in patients having extrathyroidal extension (P = 0.011) and absence of metastasis (P = 0.032). Expression of the studied SOCS proteins may be a consequence of activation of Janus kinase-signal transducers and activators of transcription and other pathways supporting growth and survival of cancer cells that are sustained by several cytokines. Thus, SOCS-1, SOCS-2, and SOCS-3 proteins may directly or indirectly, have important roles in development and pathogenesis of papillary thyroid cancer.

A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer.

Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice.

NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas.

The BRAFV600E oncogene, reported in 40%-60% of papillary thyroid cancer (PTC), has an important role in the pathogenesis of PTC. It is associated with the loss of thyroid iodide-metabolizing genes, such as sodium/iodide symporter (NIS), and therefore with radioiodine refractoriness. Inhibition of mitogen-activated protein kinase (MAPK) pathway, constitutively activated by BRAFV600E, is not always efficient in resistant tumors suggesting that other compensatory mechanisms contribute to a BRAFV600E adaptive resistance. Recent studies pointed to a key role of transforming growth factor β (TGF-β) in BRAFV600E-induced effects. The reactive oxygen species (ROS)-generating NADPH oxidase NOX4, which is increased in PTC, has been identified as a new key effector of TGF-β in cancer, suggestive of a potential role in BRAFV600E-induced thyroid tumors. Here, using two human BRAFV600E-mutated thyroid cell lines and a rat thyroid cell line expressing BRAFV600E in a conditional manner, we show that NOX4 upregulation is controlled at the transcriptional level by the oncogene via the TGF-β/Smad3 signaling pathway. Importantly, treatment of cells with NOX4-targeted siRNA downregulates BRAFV600E-induced NIS repression. Innovation and Conclusion: Our results establish a link between BRAFV600E and NOX4, which is confirmed by a comparative analysis of NOX4 expression in human (TCGA) and mouse thyroid cancers. Remarkably, analysis of human and murine BRAFV600E-mutated thyroid tumors highlights that the level of NOX4 expression is inversely correlated to thyroid differentiation suggesting that other genes involved in thyroid differentiation in addition to NIS might be silenced by a mechanism controlled by NOX4-derived ROS. This study opens a new opportunity to optimize thyroid cancer therapy. Antioxid. Redox Signal. 26, 864-877.

Abstract 3560: Bcl-Xl over-expression is a poor prognostic marker in papillary thyroid cancer and can be therapeutically targeted to induce apoptosis and autophagy

Abstract Bcl-Xl is a member of the Bcl-2 family of proteins that are divided into either pro-apoptotic proteins or anti-apoptotic proteins on the basis of their functionality. All the members of the Bcl-2 family share common domains known as Bcl-2 Homology (BH1-4) domain. The pro-apoptotic family members include proteins that only contain the BH-3 domain and include Bax, Bak, Bid, PUMA, NOXA, Bim and Bad while the anti-apoptotic proteins include members such as Bcl-2, Bcl-Xl and Mcl-1. In normal conditions, there is a balance between the pro- and anti-apoptotic members of the Bcl-2 family. Because of their important role in cell survival, there has been lot of interest in utilizing dysregulation of Bcl-2 family members to counter cancer growth and induce apoptosis. Bcl-Xl is an anti-apoptotic protein that has found to be over-expressed in various cancers including lung cancer, DLBCL and breast cancer. However, the role of Bcl-Xl in papillary thyroid cancer (PTC) from Middle Eastern region has not been fully illustrated. In order to investigate the role of Bcl-Xl in PTC, we examined the expression of Bcl-Xl in a cohort of 1022 PTC clinical cases by immunohistochemistry in a tissue microarray format and found that Bcl-Xl was over-expressed in 51.7% of PTC cases. Bcl-Xl over-expression was significantly associated with aggressive high proliferative markers such as older age (p = 0.0009), extra-thyroidal extension (p&amp;lt;0.0001), tumor size (p = 0.0081), nodal involvement (p = 0.0067), metastasis (p = 0.0013) and showed a poor overall 5 year survival (0.0438). Bcl-Xl over-expression was was also found to be significantly associated with p-AKT (p&amp;lt;0.0001), XIAP (p&amp;lt;0.0001) and proliferative marker Ki67 (p = 0.0041). In vitro, targeting Bcl-Xl expression in PTC cell lines using a small molecular inhibitor of Bcl-Xl; AB141657 (Z36) showed a dose dependent inhibition of cell viability and induction of apoptosis after 48 hours treatment. Using 5 and 10μM Z36, we found that PTC cells not only underwent apoptosis detected by flow cytometry, inactivation of AKT and activation of mitochondrial apoptotic pathway but also autophagy as detected by up-regulation of LC1-3, inactivation of p-mTOR1 and p-mTOR2 and their downstream targets. These data clearly indicate a role of Bcl-Xl in the pathogenesis of PTC as well as the importance of targeting Bcl-Xl using Z36 to induce both; apoptosis and autophagy in Bcl-Xl over-expressing PTC cells. Citation Format: Azhar R. Hussain, Maqbool Ahmed, Shaham Beg, Rong Bu, Roxanne Melosantos, Zeeshan Qadri, Saif Al-Sobhi, Fouad Al-Dayel, Abdul Khalid Siraj, Khawla S. Al-Kuraya. Bcl-Xl over-expression is a poor prognostic marker in papillary thyroid cancer and can be therapeutically targeted to induce apoptosis and autophagy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3560.

The Long Non-Coding RNA ENST00000537266 and ENST00000426615 Influence Papillary Thyroid Cancer Cell Proliferation and Motility

Background/Aims: Papillary thyroid cancer (PTC) is the most common histotype of Thyroid cancer (TC). Here, we detected the differentially expressed lncRNAs in tumor tissues and non-tumor tissues of PTC patients by lncRNA microarrays, and explored the function and molecular mechanisms of lncRNAs in the pathogenesis of PTC using a PTC cell line. Methods: CCK-8 assay, colony formation assay and EdU assay were used to detect the cell viability. Flow Cytometry was used to detect the cell cycle and apoptosis. Transwell and scratch assay were used to detect the cell motility. Results: CCK-8 assay, colony formation assay and EdU assay revealed that lncRNAs (ENST00000537266 and ENST00000426615) could inhibit cell proliferation. Cell cycle analysis showed that cell proportion was statistically significant increased in G1 phase and decreased in S phase and G2 phase in Si-266 transfected TPC-1 cells. In addition, a noteworthy increase of cell proportion in G1 phase accompanied by a decrease in S phase and unchanged G2 phase in Si-615 transfected TPC-1 cells were also observed. Meanwhile, transwell and scratch assay showed that ENST00000426615 could inhibit the cell motility while ENST00000537266 could not. Conclusion: Our results showed that lncRNAs (ENST00000426615 and ENST00000537266) might be important regulators of PTC cell proliferation and motility, which might provide new insight into the understanding of PTC pathogenesis.

MicroRNA-3151 inactivates TP53 in BRAF-mutated human malignancies

The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-κB complex. Knockdown of microRNA-3151 (miR-3151) with short hairpin RNAs reduces cell proliferation and increases apoptosis of MM and PTC cells. Using a targeted RNA sequencing approach, we mechanistically determined that miR-3151 directly targets TP53 and other members of the TP53 pathway. Reducing miR-3151's abundance increases TP53's mRNA and protein expression and favors its nuclear localization. Consequently, knockdown of miR-3151 also leads to caspase-3-dependent apoptosis. Simultaneous inhibition of aberrantly activated BRAF and knockdown of miR-3151 potentiates the effects of sole BRAF inhibition with the BRAF inhibitor vemurafenib and may provide a novel targeted therapeutic approach in BRAF-mutated MM and PTC patients. In conclusion, we identify miR-3151 as a previously unidentified player in MM and PTC pathogenesis, which is driven by BRAF-dependent and BRAF-independent mechanisms. Characterization of TP53 as a downstream effector of miR-3151 provides evidence for a causal link between BRAF mutations and TP53 inactivation.

Promoter methylation of p16 and RASSF1A genes may contribute to the risk of papillary thyroid cancer: A meta-analysis.

The aim of the present meta-analysis was to investigate the correlation of promoter methylation of the p16 and Ras association domain family 1 isoform A (RASSF1A) genes with the risk of the development of papillary thyroid cancer (PTC). A number of electronic databases were searched without language restrictions as follows: Medline (1966-2013), the Cochrane Library database (Issue 12, 2013), Embase (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and the Chinese Biomedical Database (CBM; 1982-2013). A meta-analysis was performed with the use of Stata statistical software. The odds ratios (ORs), ratio differences (RDs) and 95% confidence intervals (95% CIs) were calculated. In the present meta-analysis, eleven clinical cohort studies with a total of 734 patients with PTC were included. The results of the current meta-analysis indicated that the frequency of promoter methylation of p16 in cancer tissues was significantly higher compared with that in normal, adjacent and benign tissues (cancer tissues vs. normal tissues: OR=7.14; 95% CI, 3.30-15.47; P<0.001; cancer tissues vs. adjacent tissues: OR=11.90; 95% CI, 5.55-25.52; P<0.001; cancer tissues vs. benign tissues: OR=2.25; 95% CI, 1.67-3.03; P<0.001, respectively). The results also suggest that RASSF1A promoter methylation may be implicated in the pathogenesis of PTC (cancer tissues vs. normal tissues: RD=0.53; 95% CI, 0.42-0.64; P<0.001; cancer tissues vs. adjacent tissues: RD=0.39; 95% CI, 0.31-0.48; P<0.001; cancer tissues vs. benign tissues: RD=0.39; 95% CI, 0.31-0.47; P<0.001; respectively). Thus, the present meta-analysis indicates that aberrant promoter methylation of p16 and RASSF1A genes may play a crucial role in the pathogenesis of PTC.

Role of X-Linked Inhibitor of Apoptosis as a Prognostic Marker and Therapeutic Target in Papillary Thyroid Carcinoma.

Papillary thyroid cancer (PTC) is the second most common cancer in females in Saudi Arabia. However, the pathogenesis of PTC is still not fully elucidated. To identify potential genes that play important role in progression of PTC, we studied the role of X-linked inhibitor of apoptosis protein (XIAP) as a potential prognostic marker and therapeutic target in a large cohort of PTC samples and cell lines. A DNA microarray chip was used to screen for gene copy number. XIAP expression was assessed by immunohistochemistry in a tissue microarray format on a cohort of 1022 clinical samples. In vitro and in vivo studies were performed using Embelin and/or LY294002 on PTC cell lines. XIAP was found to be amplified in 14 of 29 and overexpressed in 48.8% of PTC cases. XIAP overexpression was significantly associated with old age, extrathyroidal extension, tumor size, nodal involvement, tall-cell variant, advanced stage disease, and significantly poor disease-free survival (P = .0341). XIAP was also significantly associated with phosphorylated AKT (P < .0001), Bcl-Xl (P < .0001), and Ki67 (P = .0006) proteins. Embelin treatment caused growth inhibition and apoptosis in PTC cell lines and induced tumor regression in PTC xenograft in nude mice. Finally, the combination of suboptimal doses of Embelin and LY294002 induced a synergistic apoptotic response in PTC cells. XIAP dysregulation in PTC confers an aggressive phenotype with poor outcome. In vitro and in vivo studies using an XIAP inhibitor suggest that this subgroup of PTC with overexpression of XIAP can be therapeutically targeted, either alone or in combination, to induce efficient apoptosis in these cancers.

Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin's lymphoma, and cancer.

The clinical course of chronic hepatitis C virus (HCV) infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinico-epidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells non-Hodgkin's lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCV-related thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients' populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases.

Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer

The etiopathogenesis of thyroid cancer has not been clearly elucidated although the role of chronical inflammation and the imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with papillary thyroid cancer (PTC), and to evaluate the relationship between genotypes and clinical/laboratory manifestation of PTC. Tumor necrosis factorα (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 A-1082G (rs 1800896) single nucleotide polymorphisms in DNA from peripheral blood leukocytes of 190 patients with thyroid cancer and 216 healthy controls were investigated by real-time PCR combined with melting curve analysis. There was no notable risk for PTC afflicted by TNFα-308 and IL-6-174 alone. However, IL-10-1082 G allele frequency were higher among PTC patients than healthy controls (p=0.009). The patients with IL-10-1082 GG geotype have twofold increased risk of developing thyroid cancer according to AA genotype (OR 2.07, 95% CI 1.21-3.55). In addition, the concomitant presence of IL-10-1082 G allele (GG+AG genotypes) together with IL-6 -174 GG genotype has a nearly twofold increased risk for thyroid cancer (OR 1.75 with 95% CI 1.00-3.05, p=0.049). We suggest that IL-10-1082 G allele is associated with an increased risk of PTC. The polymorphism of IL-10 gene can improve our knowledge about the pathogenesis of PTC, and could provide to estimate people at the increased risk for PTC.