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. Rehmet, Kristina de Souza Gomes, Matheus Fort, Antoine Kovvuru, Prasad Muniyappa, Mohan K. Kerin, Michael J. Enright, Anton J. Spillane, Charles
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
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Publication Date
2012-07-02
Type
Article
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Citation
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
Abstract
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.
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Publisher
American Society for Biochemistry & Molecular Biology (ASBMB)
Publisher DOI
10.1074/jbc.m111.335943
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland