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Molecular Cancer

, 16:88

First Online: 10 May 2017Received: 30 September 2016Accepted: 24 April 2017DOI: 10.1186-s12943-017-0655-2

Cite this article as: Bellissimo, T., Ganci, F., Gallo, E. et al. Mol Cancer 2017 16: 88. doi:10.1186-s12943-017-0655-2

Abstract

BackgroundThymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors TETs. A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA miRNAs differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation.

MethodsmRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma TC1889 cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid VPA.

ResultsStarting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib.

ConclusionsAltogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

KeywordsmicroRNA Thymic epithelial tumors miR-145-5p Thymoma Thymic carcinoma Epigenetic regulation AbbreviationsCDDPCisplatin

CDH2N-cadherin

ChIPChromatin Immunoprecipitation

CK19Cytokeratin 19

DsiRNAsDicer-substrate short interfering RNAs

EGFEpithelial growth factor

EGFREpidermal growth factor receptor

FFPEFormalin-fixed paraffin embedded

Golm1Golgi membrane protein 1

HDACsHistone deacetylases

IHCImmunohistochemistry

INH-145miR-145-5p inhibitor

INH-CScramble inhibitor

miRNAsmicroRNAs

MPMMalignant pleural mesothelioma

PCAPrincipal component analysis

TCThymic carcinoma

TETTumor epithelial tissues

VPAValproic acid

WHOWorld Health Organization

Electronic supplementary materialThe online version of this article doi:10.1186-s12943-017-0655-2 contains supplementary material, which is available to authorized users.





Autor: Teresa Bellissimo - Federica Ganci - Enzo Gallo - Andrea Sacconi - Claudia Tito - Luciana De Angelis - Claudio Pulito - Sil

Fuente: https://link.springer.com/



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