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Overexpression of microRNA-375 in medullary thyroid carcinoma cells hinders cell proliferation and improves the vandetanib efficacy effect in vitro

ABSTRACT: The global microRNA (miRNA) profiling expression was assessed in a large series of both sporadic and hereditary forms of medullary thyroid carcinomas (MTC), and to evaluate the biological function of major found altered miRNAs. For this purpose we investigated miRNA differential expression in tumoral vs adjacent non tumoral tissues from 62 MTC patients, and showed a specific overexpression of miR-375, -129-3p, -376c, -335, -96, -10a, -7, -429 and an underexpression of miR-451 in tumoral tissues. Since miR-375 was the most up-regulated miRNA, we thus decided to identify its targets by combining a transcriptomic signature of cells transfected either with premiR- or antagomiR-375 and an in silico analysis joining TT-cells mRNA specific signature from Cancer Cell Line Encyclopedia GEO dataset and miRNA prediction algorithms. Using this restrictive approach, we focused on miR-375 target SEC23A and validated a decreased expression of SEC23A by Western blotting and by immunohistochemistry in tumoral vs non tumoral adjacent thyroid epithelium. Furthermore, we observed that overexpression of miR-375 was associated with decreased proliferation and increased vandetanib response in vitro. Overall, our results showed an overexpression of miR-375 in MTC in association with a decrease of miR-375-potential targets including SEC23A. Additionnally, we postulate thatmiR-375 overexpression should be evaluated in MTC patients treated with the tyrosine kinase inhibitor, vandetanib.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67742 | GEO | 2016/05/22

SECONDARY ACCESSION(S): PRJNA280808

REPOSITORIES: GEO

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Project description:In this study we performed a systematic evaluation of functional miRNA-mRNA interactions associated with the aggressiveness of breast cancer cells using a combination of integrated miRNA and mRNA expression profiling, bioinformatics prediction, and functional assays. Analysis of the miRNA expression identified 11 miRNAs that were differentially expressed, including 7 down-regulated (miR-200c, miR-205, miR-203, miR-141, miR-34a, miR-183, and miR-375) and 4 up-regulated miRNAs (miR-146a, miR-138, miR-125b1 and miR-100), in aggressive cell lines when compared to normal and less aggressive cell lines. Transient overexpression of miR-200c, miR-205, and miR-375 in MDA-MB-231 cells led to the inhibition of cell migration and invasion. The integrated analysis of miRNA and mRNA expression identified 35 known and novel target genes of miR-200c, miR-205, and mir-375, including CFL2, LAMC1, TIMP2, ZEB1, CDH11, PRKCA, PTPRJ, PTPRM, LDHB, and SEC23A. Surprisingly, the majority of these genes (27 genes) were target genes of miR-200c, suggesting that it plays a more important role in regulating the aggressiveness of breast cancer cells. We characterized one of the target genes of miR-200c, CFL2, and demonstrated that CFL2 is overexpressed in aggressive breast cancer cell lines and can be significantly down-regulated by exogenous miR-200c. Tissue microarray analysis further revealed that CFL2 expression in primary breast cancer tissue correlated with tumor grade. To our knowledge, this study is the first systematic screening of functional miRNA target genes in aggressive breast cancer cells. The results obtained from this study may improve our understanding of the role of these candidate miRNAs and their target genes in relation to breast cancer aggressiveness and ultimately lead to the identification of novel biomarkers associated with prognosis. Affymetrix miRNA 1.0 arrays were performed according to the manufacturer's directions on small RNA extracted from 12 breast cancer cell lines including 4 aggressive cell lines, 6 less aggressive cell lines and 2 imortalized breast epithelium cell lines

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Overexpression of microRNA-375 in medullary thyroid carcinoma cells hinders cell proliferation and improves the vandetanib efficacy effect in vitro

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