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      Identification of RNA Expression Profiles in Thyroid Cancer to Construct a Competing Endogenous RNA (ceRNA) Network of mRNAs, Long Noncoding RNAs (lncRNAs), and microRNAs (miRNAs)

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          Abstract

          Background

          The aims of this study were to use RNA expression profile bioinformatics data from cases of thyroid cancer from the Cancer Genome Atlas (TCGA), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Gene Ontology (GO) databases to construct a competing endogenous RNA (ceRNA) network of mRNAs, long noncoding RNAs (lncRNAs), and microRNAs (miRNAs).

          Material/Methods

          TCGA provided RNA profiles from 515 thyroid cancer tissues and 56 normal thyroid tissues. The DESeq R package analyzed high-throughput sequencing data on differentially expressed RNAs. GO and KEGG pathway analysis used the DAVID 6.8 and the ClusterProfile R package. Kaplan-Meier survival statistics and Cox regression analysis were performed. The thyroid cancer ceRNA network was constructed based on the miRDB, miRTarBase, and TargetScan databases.

          Results

          There were 1,098 mRNAs associated with thyroid cancer; 101 mRNAs were associated with overall survival (OS). Multivariate analysis developed a risk scoring system that identified seven signature mRNAs, with a discriminative value of 0.88, determined by receiver operating characteristic (ROC) curve analysis. A ceRNA network included 13 mRNAs, 31 lncRNAs, and seven miRNAs. Four out of the 31 lncRNAs and all miRNAs were down-regulated, and the remaining RNAs were upregulated. Two lncRNAs (MIR1281A2HG and OPCML-IT1) and one miRNA (miR-184) were significantly associated with OS in patients with thyroid cancer.

          Conclusions

          Differential RNA expression profiling in thyroid cancer was used to construct a ceRNA network of mRNAs, lncRNAs, and miRNAs that showed potential in evaluating prognosis.

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          Most cited references18

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          miRTarBase update 2014: an information resource for experimentally validated miRNA-target interactions

          MicroRNAs (miRNAs) are small non-coding RNA molecules capable of negatively regulating gene expression to control many cellular mechanisms. The miRTarBase database (http://mirtarbase.mbc.nctu.edu.tw/) provides the most current and comprehensive information of experimentally validated miRNA-target interactions. The database was launched in 2010 with data sources for >100 published studies in the identification of miRNA targets, molecular networks of miRNA targets and systems biology, and the current release (2013, version 4) includes significant expansions and enhancements over the initial release (2010, version 1). This article reports the current status of and recent improvements to the database, including (i) a 14-fold increase to miRNA-target interaction entries, (ii) a miRNA-target network, (iii) expression profile of miRNA and its target gene, (iv) miRNA target-associated diseases and (v) additional utilities including an upgrade reminder and an error reporting/user feedback system.
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            Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature.

            Recently, a somatic point mutation of the B-RAF gene (V600E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC), with a prevalence variable among different series. Since discordant data on the clinico-pathologic features of B-RAF mutated PTC are present in the literature, the aim of the present co-operative study was to establish the prevalence of this genetic alteration and to perform a genotype-phenotype correlation in a large cohort of patients with PTC. To this purpose, a series of 260 sporadic PTCs with different histological variants were included in the study. The mutational analysis of the B-RAF gene was performed either by RT-PCR followed by single-stranded conformational polymorphism or by PCR and direct sequencing. Statistical analyses were obtained by means of chi2/Fisher's exact test and t-test. Overall, a heterozygous T > A transversion at nucleotide 1799 (V600E) was found in 99 out of 260 PTCs (38%). According to the histological type of the tumor, the B-RAF (V600E) mutation was present in 48.3% of cases of classic PTCs (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTCs, in 21.7% (five out of 23) in other PTC variants and in none of the ten poorly differentiated tumors. B-RAF (V600E) was significantly associated with the classic variant of PTC (P = 0.0001) and with an older age at diagnosis (P = 0.01). No statistically significant correlation was found among the presence of B-RAF (V600E) and gender, tumor node metastasis (TNM), multicentricity of the tumor, stage at diagnosis and outcome. In conclusion, the present study reports the prevalence of B-RAF (V600E) (38%) in the largest series of sporadic PTCs, including 260 cases from three different Italian referring centers. This prevalence is similar to that calculated by pooling together all data previously reported, 39.6% (759 out of 1914 cases), thus indicating that the prevalence of this genetic event lies around 38-40%. Furthermore, B-RAF (V600E) was confirmed to be associated with the papillary growth pattern, but not with poorer differentiated PTC variants. A significant association of B-RAF mutation was also found with an older age at diagnosis, the mutation being very rare in childhood and adolescent PTCs. Finally, no correlation was found with a poorer prognosis and a worse outcome after a median follow-up of 72 months.
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              LncRNA Gas5 acts as a ceRNA to regulate PTEN expression by sponging miR-222-3p in papillary thyroid carcinoma

              Accumulating evidence demonstrates that the long non-coding RNA Growth Arrest-Specific 5 (Gas5) has practical significance in cancer progression and metastasis. However, its role and function in papillary thyroid carcinoma (PTC) remains unknown. In this study, we aimed to explore the potential involvement of Gas5 in papillary thyroid carcinogenesis and to highlight the emerging roles of ceRNAs in the biological regulation of PTC cells. The results suggested that Gas5 was markedly downregulated in both PTC tissues and PTC cell lines. Over-expression of Gas5 remarkably suppressed PTC cells proliferation in vitro and inhibited the growth of tumor cells in vivo likewise. Furthermore, Gas5 was identified as a target of miR-222-3p which was aberrantly high in PTC cells. Enhanced expression of miR-222-3p promoted the proliferation of PTC cells while knocking down miR-222-3p could inhibit it. The advanced effects of miR-222-3p on the proliferation of PTC cells could be partly reversed by the upregulation of Gas5 expression. Furthermore, we validated that Gas5 increased the protein level of the PTEN, one of miR-222-3p’s targets, which further activated PTEN/AKT pathway. Taken together, our study identified a tumor suppressive role of Gas5 in PTC cells acting as a ceRNA, effectively becoming a sink for miR-222-3p, modulating the expression of PTEN, which lead to PTEN/AKT pathway activation and proliferation suppression. This finding may offer a new potential therapeutic strategy for PTC.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2019
                12 February 2019
                : 25
                : 1140-1154
                Affiliations
                [1 ]Department of Endocrinology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China
                [2 ]Harbin Medical University, Harbin, Heilongjiang, P.R. China
                [3 ]Department of Public Health Sciences, Stockholm University, Stockholm, Sweden
                [4 ]Department of Nursing, The Hospital of Heilongjiang Province, Harbin, Heilongjiang, P.R. China
                Author notes
                Corresponding Author: Lihua Xu, e-mail: Lihua_xu63@ 123456outlook.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                912450
                10.12659/MSM.912450
                6380385
                30745559
                648ff3ad-8201-47cd-b2f8-ee2da5ee89cc
                © Med Sci Monit, 2019

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                History
                : 01 August 2018
                : 12 October 2018
                Categories
                Lab/In Vitro Research

                carcinogenesis,gene expression profiling,micrornas,rna, long noncoding,thyroid neoplasms

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