Microrna-143 is a potential tumor suppressor targeting DNA methyltransferases 3A in breast cancer

Abstract

BACKGROUND AND AIMS: MicroRNAs (miRNAs) are 19-25-nucleotides regulatory non-protein-coding RNA molecules that regulate the expressions of a wide variety of genes including some involved in cancer development. Down-regulation of miR-143 has been reported in various human cancers including colorectal cancer and B-cell lymphomas. The aim of this study was to elucidate the role of miR-143 deregulation in breast cancer. METHODS: Down-regulation of miR-143 was evaluated in breast cancer cell lines and paired breast tumors and normal tissues by quantitative RT-PCR. Potential targets of miR-143 were defined. The functional effect of the miR-143 and its targets was performed in human breast cancer cell lines to confirm target association. RESULTS: Down-regulation of miR-143 was verified in both human breast cancer cell lines and 80% (12/15) of breast tumors (P < 0.001). Using in-silico predictions, DNA methyltranferase 3A (DNMT3A), one of a key enzyme involved in DNA methylation, was defined as a downstream potential target of miR-143. Restoration of miR-143 expression in breast cancer cell lines down-regulated expression of DNMT3A. DNMT3A was demonstrated to be a direct target of miR-143 by luciferase reporter assay. Expressions of DNMT3A and miR-143 were inversely correlated in tumor and normal breast tissues. CONCLUSIONS: In this study, we show for the first time that miR-143 specifically targeted DNMT3A and the expression of miR-143 was inversely correlated with DNMT3A expression in breast cancer. Our findings demonstrated that down-regulation of miR-143 and up-regulation of DNMT3A are significant changes in breast tumors. These findings point to a tumor suppressive role of miR-143 in epigenetic aberration of breast cancer, pointing to miRNA-based targeted approaches for breast cancer therapy.