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      CXCL12 methylation-mediated epigenetic regulation of gene expression in papillary thyroid carcinoma

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          Abstract

          Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence rate is rapidly growing. It is necessary to understand the pathogenesis of PTC to develop effective diagnosis methods. Promoter methylation has been recognized to contribute to the alterations in gene expression observed in tumorigenesis. Our RNA-seq data identified 1191 differentially expressed mRNAs and 147 differentially expressed lncRNAs in PTC. Next, promoter methylation of these genes was detected by reduced representation bisulfite sequencing (RRBS) technology and comprehensively analyzed to identify differential methylation. In total, 14 genes (13 mRNAs and 1 lncRNA), in which methylation was intimately involved in regulating gene expression, were proposed as novel diagnostic biomarkers. To gain insights into the relationships among these 14 genes, a core co-function network was constructed based on co-expression, co-function and co-methylation data. Notably, CXCL12 was identified as an essential gene in the network that was closely connected with the other genes. These data suggested that CXCL12 down-regulation in PTC may be caused by promoter hypermethylation. Our study was the first to perform an RRBS analysis for PTC and suggested that CXCL12 may contribute to PTC development by methylation-mediated epigenetic regulation of gene expression.

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          Most cited references29

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          CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression.

          Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.
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            Coverage recommendations for methylation analysis by whole genome bisulfite sequencing

            Whole genome bisulfite sequencing (WGBS) allows genome-wide DNA methylation profiling but the associated high sequencing costs continue to limit its widespread application. We utilized several high coverage reference data sets to experimentally determine minimal sequencing requirements. Here, we present data derived recommendations for minimum sequencing depth for WGBS libraries, highlight what is gained with increasing coverage and discuss the trade off between sequencing depth and number of assayed replicates.
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              Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma.

              There are no known effective and reliable biomarkers to distinguish benign thyroid nodules from papillary thyroid carcinomas (PTC). Previous studies have indicated that serum microRNA (miRNA) profiles may be diagnostic and/or prognostic markers for numerous other cancers. We studied circulating miRNA profiles in patients with PTC or benign nodules and healthy controls to identify serum miRNA that may be useful as markers for PTC. Genome-wide serum miRNA expression profiles were determined using Solexa sequencing followed by extensive quantitative RT-PCR validation in 245 subjects (106 patients with PTC, 95 patients with benign nodules, and 44 healthy controls). A panel of miRNA was used to assess the expression of specific miRNA in the sera and thyroid tissues of patients with PTC or benign nodules. The expression of serum let-7e, miR-151-5p, and miR-222 was significantly increased in PTC cases relative to benign cases and healthy controls. Receiver operating characteristic curve analyses indicated that use of these three miRNA had a high diagnostic sensitivity and specificity for PTC. Serum let-7e, miR-151-5p, and miR-222 levels were found to be well correlated with certain clinicopathological variables, such as nodal status, tumor size, multifocal lesion status, and Tumor-Node-Metastasis stage. Expression of serum miR-151-5p and miR-222 in a subset of PTC patients decreased significantly after tumor excision. Increased expression of miR-151-5p and miR-222 was also found in the tissue of PTC patients. Our study demonstrates that serum miRNA profiles may be used as novel and minimally invasive diagnostic markers for PTC.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                08 March 2017
                2017
                : 7
                : 44033
                Affiliations
                [1 ]Department of Endoerinology and Metabolism, The Second Affiliated Hospital, Harbin Medical University , Harbin 150001, China
                [2 ]College of Bioinformatics Science and Technology, Harbin Medical University , Harbin, 150081, China
                Author notes
                Article
                srep44033
                10.1038/srep44033
                5356381
                28272462
                2fa6925f-97b3-4c4b-ab64-3cbed49a453f
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 30 September 2016
                : 31 January 2017
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