Aberrant expression of miR-21, miR-376c and miR-145 and their target host genes in Merkel cell polyomavirus-positive non-small cell lung cancer

// Ismini Lasithiotaki 1, 2 , Eliza Tsitoura 2, 3 , Anastasios Koutsopoulos 4 , Eleni Lagoudaki 4 , Chara Koutoulaki 2 , George Pitsidianakis 1 , Demetrios A. Spandidos 3 , Nikolaos M. Siafakas 1 , George Sourvinos 3, * and Katerina M. Antoniou 1, 2, * 1 Department of Thoracic Medicine, University Hospital, Medical School, University of Crete, Heraklion 71110, Greece 2 Laboratory of Cellular and Molecular Pneumonology, Medical School, University of Crete, Heraklion Crete 71110, Greece 3 Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion Crete 71110, Greece 4 Department of Pathology, Medical School, University of Crete, Heraklion Crete 71110, Greece * These authors have contributed equally to this work Correspondence to: George Sourvinos, email: sourvino@med.uoc.gr Keywords: merkel cell polyomavirus; non-small cell lung cancer; microRNAs; signalling pathways Received: April 23, 2016     Accepted: July 19, 2016     Published: August 11, 2016 ABSTRACT Merkel Cell Polyoma Virus (MCPyV) infection has been associated with non-small cell lung cancer (NSCLC). Viruses can manipulate cellular miRNAs or have a profound impact on cellular miRNA expression to control host regulatory pathways. In this study, we evaluated the expression profiles of cancer-associated and virally affected host microRNAs miR-21, miR-145, miR-146a, miR-155, miR-302c, miR-367 and miR-376c in a series of NSCLC tissue samples as well as in samples from “healthy” sites, distant from the tumour region that were either positive or negative for MCPyV DNA. miR-21 and miR-376c were significantly upregulated whereas miR-145 was significantly downregulated in the MCPyV+ve samples compared to the MCPyV-ve tumour samples. Overall, miR-21 and miR-376c expression was higher in tumour compared to healthy tissue samples. No association was observed between the miR-155, miR-146a, miR-302c and miR-367 levels and the presence of MCPyV. The expression of miR-21 target genes ( Pten, Bcl-2, Daxx, Pkr, Timp3) , miR-376c ( Grb2, Alk7 , Mmp9 ) and miR-145 ( Oct-4, Sox2 , Fascin1 ) and their associated pathways ( Braf, Akt-1, Akt-2, Bax, Hif1a, p53 ) was altered between MCPyV+ve tumor samples and their corresponding controls. These results show a novel association between miR-21, miR-376c and miR-145 and their host target genes with the presence of MCPyV, suggesting a mechanism of virus-specific microRNA signature in NSCLC.