Abstract
Hsa-miRNA-206 (miR-206), highly expressed in skeletal muscle, has recently been discovered to have anticancer properties in different tissues. However, the role of miR-206 on lung cancer is still ambiguous. In this study, we investigated the role of miR-206 on the development of lung cancer. The results indicated that miR-206 expression was suppressed in lung cancer tissues and very low levels were found in non-small cell lung cancer (NSCLS) cell lines. Transient transfection of miR-206 into cultured A549 and SK-MES-1 cells led to significant decrease in cell growth, migration, invasion and colony formation, and promoted cell apoptosis. Using bioinformatics, we identified putative miR-206 binding sites within the 3'-untranslated region (3'-UTR) of the human c-Met and Bcl2 mRNA. The expression of c-Met and Bcl2 proteins were shown to be down-regulated after treated with miR-206 by subsequent Western blot and qRT-PCR analysis. Conversely, up-regulation of c-Met and Bcl2 were confirmed in tissue samples of human lung cancer, with its level inversely correlated with miR-206 expression. In addition, miR-206 also decreased the gene expression of MMP-9, CCND1 and CCND2 while increased the gene expression of p57 (Kip2) in A549 and SK-MES-1 cells. Taken together, our results demonstrated that miR-206 suppressed c-Met and Bcl2 expression in NSCLS and could function as a potent tumor suppressor in c-Met/Bcl2-over expressing tumors. Inhibition of miR-206 function could contribute to aberrant cell proliferation, migration, invasion and apoptosis, leading to NSCLS development.
Highlights
Lung cancer is the leading cause of cancer-related deaths both in men and women around the world for several decades
We show for the first time that miR-206 directly targets and regulates the full-length 3′-untranslated region (3′-untranslated region (UTR)) of the human BCL2 (B-cell lymphoma-2) gene, and confirmed that miR-206 directly targets and regulates the full-length 3′-UTR of the human MET mRNA, which are up-regulated in many cancers, including lung cancer. c-Met is encoded by MET gene, and plays a key role in the control of invasive growth during tumorigenesis and in embryonic development, organ development, and inflammatory response [25]
Expression of c-Met, Bcl2 and cyclin D1 are up-regulated in primary human lung cancer c-Met, Bcl2 and cyclin D1 are important oncogene that shown strong power of oncogenicity, by promotion of cell growth, migration, invasion and epithelial www.impactjournals.com/oncotarget mesenchymal transition (EMT), as well as inhibition of cell apoptosis in many tumors including lung cancer [20, 26, 27]
Summary
Lung cancer is the leading cause of cancer-related deaths both in men and women around the world for several decades. At early stages of NSCLS, the only treatment is surgery, with a 5-year overall survival rate of 40% [2], whereas chemotherapy is www.impactjournals.com/oncotarget mostly employed for small cell lung cancer (SCLS). These changes are attributed to silencing of tumor suppressor genes, dysregulation of proto-oncogenes, and an up-regulation of genes that promote cell growth and transformation and tumor development [3]. MiRNAs, a class of ~20 – 23 nucleotide (nt) noncoding RNAs, repress the expression of their target genes through binding mRNAs at specific sequences. They regulate gene expression in multiple biological and pathological processes, including cell proliferation, apoptosis, heart disease, neurological disorders and human cancers [10, 11]
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