Involvement of miR-214 and miR-375 in Malignant Features of Non-Small-Cell Lung Cancer by Down-Regulating CADM1

Megumi Ishimura, Mika Sakurai-Yageta, Tomoko Maruyama, Tomoko Ando, Masashi Fukayama, Akiteru Goto, Yoshinori Murakami

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Division of Molecular Pathology, The University of Tokyo, Tokyo, Japan.
Laboratory of Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

DOI: 10.4236/jct.2012.324050                

Abstract

A tumor suppressor gene, CADM1, encoding an immunoglobulin superfamily cell adhesion molecule, is inactivated in various cancers, including non-small-cell lung cancer (NSCLC). Although promoter methylation is one of the mechanisms to suppress CADM1 expression, about half of tumors lacking CADM1 expression do not show methylation of the gene promoter. We herein investigated the possible involvement of microRNA (miRNA) in the down-regulation of CADM1. Using computational algorithms, miR-214 and miR-375 were identified as candidate miRNAs targeting CADM1. A luciferase reporter assay demonstrated that miR-214 and miR-375 repressed the promoter activity through 3’-UTR of CADM1. Quantitative RT-PCR analysis demonstrated that miR-214 and miR-375 was highly expressed in 21 (62%) and 17 cases (50%) of 34 primary NSCLCs. Notably, increased expression of miR-214 was preferentially observed in tumors with advanced pathological stages and in those lacking CADM1 expression but were not associated with the promoter methylation, suggesting that miR-214-mediated silencing would be another mechanism to suppress CADM1 expression. On the other hand, introduction of miR-214 or miR-375 into NSCLC cells decreased CADM1 protein expression. Furthermore, overexpression of miR-214 enhanced anchorage-independent growth of NSCLC cells, A549, whereas transfection of miRNA inhibitor, miR-214 or miR-375, significantly suppressed the in vitro wound healing activity of HCC827 cells. These findings suggest that overexpression of miR-214 and miR-375 could participate in the malignant features of NSCLC through down-regulating CADM1 and would provide a potential target for the treatment of a subset of NSCLC.

Keywords

CADM1; miR-214; miR-375; Non-Small-Cell Lung Cancer

Conflicts of Interest

The authors declare no conflicts of interest.

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