MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11

// Vinayakumar Siragam 1 , 4,* Zina Jeyapalan Rutnam 1 , 4,* , Weining Yang 2 , Ling Fang 1 , 4 , Linlin Luo 2 , Xiangling Yang 1 , 4 , Minhui Li 1 , 4 , Zhaoqun Deng 1 , 4 , Jun Qian 3 , Chun Peng 2 , and Burton B. Yang 1 , 4 1 Sunnybrook Research Institute, Sunnybrook Health Sciences Centre 2 Departments of Biology, York University 3 The Affiliated People’s Hospital of Jiangsu University, Zhenjiang City, China 4 Department of Laboratory Medicine and Pathobiology, University of Toronto * denotes equal contribution Correspondence: Burton B. Yang, email: // Keywords : microRNA, miR-98, angiogenesis, tumorigenesis, invasion Received : October 22, 2012, Accepted : November 02, 2012, Published : November 06, 2012 Abstract Angiogenesis and invasion are essential processes for solid tumor growth and dissemination. The tumor development process can be dependent on the activation of a series of signaling pathways, including growth factor-activated pathways. MicroRNAs have been shown to be critical for tumorigenesis, but their roles in cancer angiogenesis, invasion and other signaling pathways important for tumor development are still unclear in the context of tumor biology. We investigated the role of microRNA miR-98 in regulating tumor growth, invasion, and angiogenesis using a highly aggressive breast cancer model in vitro and in vitro. We found that the expression of miR-98 inhibited breast cancer cell proliferation, survival, tumor growth, invasion, and angiogenesis. Conversely, inhibition of endogenous miR-98 promoted cell proliferation, survival, tumor growth, invasion, and angiogenesis. It appeared that miR-98 inhibited angiogenesis by modulating endothelial cell activities including cell spreading, cell invasion and tubule formation. Interestingly, miR-98 reduced the expression of ALK4 and MMP11, both of which were potential targets of miR-98. Transfection of an anti-miR-98 construct increased the expression of both targets. We confirmed that mir-98 targeted the 3’-untranslated regions of ALK4 and MMP11. Finally, ALK4- and MMP11-specific siRNAs inhibited breast cancer cell proliferation, survival, and angiogenesis. Rescue experiments with ALK4 and MMP11 constructs reversed the anti-proliferative, anti-invasive and anti-angiogenic effects of miR-98. Our findings define a regulatory role of miR-98 in tumor angiogenesis and invasion through repressed ALK4 and MMP11 expression.