miR-656 inhibits glioma tumorigenesis through repression of BMPR1A

Abstract

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, plays critical roles in cell differentiation, modeling and regeneration processes in several tissues. BMP-2 is also closely associated with various malignant tumors. microRNAs negatively and posttranscriptionally regulate gene expression and function as oncogenes or tumor suppressors. Herein, we report that miR-656 expression was significantly downregulated in glioma cell lines and tissues. We identified and confirmed that BMP receptor, type 1A (BMPR1A) is a direct target of miR-656. The expression of BMPR1A was negatively correlated with that of miR-656 in human glioma tissues. We further demonstrated that miR-656 suppressed glioma cell proliferation, neurosphere formation, migration and invasion with or without exogenous BMP-2. Engineered knockdown of BMPR1A diminished the antiproliferation effect of miR-656 in vitro. Moreover, the canonical BMP/Smad and non-canonical BMP/mitogen-activated protein kinase (MAPK) pathways were inhibited by miR-656 overexpression. Several cancer-related signaling molecules, including cyclin B, cyclin D1, matrix metalloproteinase-9, p21 and p27, were also involved in miR-656 function in glioma cells. The tumor-suppressing function of miR-656 was validated using an in vivo intracranial xenograft mouse model. Notably, ectopic expression of miR-656 markedly reduced tumor size and prolonged the survival of mice treated with or without BMP-2. These results elucidate the function of miR-656 in glioma progression and suggest a promising application for glioma treatment.