title: MicroRNA miR-98 inhibits tumor angiogenesis and invasion by targeting activin receptor-like kinase-4 and matrix metalloproteinase-11.
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.
authors.affiliation: Sunnybrook Health Sciences Centre, University of Toronto, Canada.
authors.forename: Vinayakumar
authors.initials: V
authors.lastname: Siragam
authors.forename: Zina Jeyapalan
authors.initials: ZJ
authors.lastname: Rutnam
authors.forename: Weining
authors.initials: W
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Fang
authors.forename: Linlin
authors.initials: L
authors.lastname: Luo
authors.forename: Xiangling
authors.initials: X
authors.lastname: Yang
authors.forename: Minhui
authors.initials: M
authors.lastname: Li
authors.forename: Zhaoqun
authors.initials: Z
authors.lastname: Deng
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Chun
authors.initials: C
authors.lastname: Peng
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions; D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000628:therapy; D053507:Matrix Metalloproteinase 11 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C546084:MIRN98 microRNA, human; D035683:MicroRNAs; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D053507:Matrix Metalloproteinase 11