Microrna-9 inhibition of cell proliferation and identification of novel mir-9 targets by transcriptome profiling in breast cancer cells
Selcuklu, S. Duygu
Donoghue, Mark T. A.
de Souza Gomes, Matheus
Muniyappa, Mohan K.
Kerin, Michael J.
Enright, Anton J.
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Selcuklu, S. Duygu; Donoghue, Mark T. A. Rehmet, Kristina; de Souza Gomes, Matheus; Fort, Antoine; Kovvuru, Prasad; Muniyappa, Mohan K.; Kerin, Michael J.; Enright, Anton J.; Spillane, Charles (2012). Microrna-9 inhibition of cell proliferation and identification of novel mir-9 targets by transcriptome profiling in breast cancer cells. Journal of Biological Chemistry 287 (35), 29516-29528
Although underexpression of miR-9 in cancer cells is reported in many cancer types, it is currently difficult to classify miR-9 as a tumor suppressor or an oncomir. We demonstrate that miR-9 expression is down-regulated in MCF-7 and MDA-MB-231 breast cancer cells compared with MCF-10-2A normal breast cell line. Increasing miR-9 expression levels in breast cancer cells induced anti-proliferative, anti-invasive, and pro-apoptotic activity. In addition, microarray profiling of the transcriptome of MCF-7 cells overexpressing miR-9 identified six novel direct miR-9 targets (AP3B1, CCNG1, LARP1, MTHFD1L, MTHFD2, and SRPK1). Among these, MTHFD2 was identified as a miR-9 target gene that affects cell proliferation. Knockdown of MTHFD2 mimicked the effect observed when miR-9 was overexpressed by decreasing cell viability and increasing apoptotic activity. Despite variable effects on different cell lines, proliferative and anti-apoptotic activity of MTHFD2 was demonstrated whereby it could escape from miR-9-directed suppression (by overexpression of MTHFD2 with mutated miR-9 binding sites). Furthermore, endogenous expression levels of miR-9 and MTHFD2 displayed inverse expression profiles in primary breast tumor samples compared with normal breast samples; miR-9 was down-regulated, and MTHFD2 was up-regulated. These results indicate anti-proliferative and pro-apoptotic activity of miR-9 and that direct targeting of MTHFD2 can contribute to tumor suppressor-like activity of miR-9 in breast cancer cells.