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.

Signaling Receptors for TGF-β Family Members

“…During erythropoiesis, the ALK-4 mRNA is targeted by miR-24; ALK-4 down-regulation is required so that early stages of erythroid cell differentiation can progress . During breast cancer invasion and angiogenesis, the ALK-4 mRNA is down-regulated by miR-98; because ALK-4 positively contributes to breast cancer metastasis, miR-98 acts as a metastasis suppressor (Siragam et al 2012). Finally, in ovarian cancers, the nodal/ALK-7 tumor suppressor pathway is inactivated by miR-376c, which down-regulates the ALK-7 receptor, showing that miR-376c has a protumorigenic effect (Ye et al 2011).…”

miR-17-5p down-regulation contributes to erlotinib resistance in non-small cell lung cancer cells

“…In the last decade, numerous microRNAs (miRNAs) have been identified and they play important roles in diverse cellular processes in development and disease by modulating gene expression at the post-transcriptional level [9]. And they also were reported to involve in tumor proliferation, invasion, angiogenesis, and drug resistance [10][11][12][13][14]. The miRNAs can induce target mRNA degradation and translational repression through its recognition elements pairing to 3 0 -untranslated region (3 0 -UTR) of the target mRNAs [15,16].…”

MicroRNA miR-24 Enhances Tumor Invasion and Metastasis by Targeting PTPN9 and PTPRF to Promote EGF Signaling

“…Through binding to the 39-untranslated region (39UTR) of different target mRNAs (mRNAs), microRNAs can repress the translation of the target mRNAs (Seitz et al, 2003). As a new class of regulatory molecules, miRNAs have diverse functions in cell proliferation Viticchiè et al, 2011;Yu et al, 2012), survival (Fang et al, 2012a;Ye et al, 2011), invasion Luo et al, 2012;Siragam et al, 2012), cell differentiation (Goljanek-Whysall et al, 2012;Kahai et al, 2009;Rutnam and Yang, 2012b), morphogenesis (Wang et al, 2008a), tissue growth (Shan et al, 2009), angiogenesis Lee et al, 2007;Smits et al, 2010;Zou et al, 2012), tumor development (Nohata et al, 2012;Volinia et al, 2006) and metastasis (Huang et al, 2008;Ma et al, 2007;Rutnam and Yang, 2012a). The largest functional group of miRNAs is the one involved in cancer development.…”