Guo Mian, Jiang Zhenfeng, Zhang Xiaoming, Lu Dunyue, Ha Albert Duy, Sun Jiahang, Du Wenzhong, Wu Zhichao, Hu Li, Khadarian Kevork, Shen Jia, Lin Zhiguo
Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Carcinogenesis. 2014 Aug;35(8):1698-706. doi: 10.1093/carcin/bgu030. Epub 2014 Jan 30.
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.
骨形态发生蛋白2（BMP-2）是转化生长因子-β家族的成员，在多种组织的细胞分化、塑形和再生过程中发挥关键作用。BMP-2还与多种恶性肿瘤密切相关。微小RNA在转录后对基因表达起负调控作用，可作为癌基因或肿瘤抑制因子发挥作用。在此，我们报道miR-656在胶质瘤细胞系和组织中的表达显著下调。我们鉴定并证实骨形态发生蛋白受体1A（BMPR1A）是miR-656的直接靶点。在人类胶质瘤组织中，BMPR1A的表达与miR-656的表达呈负相关。我们进一步证明，无论有无外源性BMP-2，miR-656均可抑制胶质瘤细胞的增殖、神经球形成、迁移和侵袭。通过工程手段敲低BMPR1A可减弱miR-656在体外的抗增殖作用。此外，miR-656过表达可抑制经典的BMP/Smad和非经典的BMP/丝裂原活化蛋白激酶（MAPK）信号通路。包括细胞周期蛋白B、细胞周期蛋白D1、基质金属蛋白酶-9、p21和p27在内的几种癌症相关信号分子也参与了miR-656在胶质瘤细胞中的功能。使用体内颅内异种移植小鼠模型验证了miR-656的肿瘤抑制功能。值得注意的是，miR-656的异位表达显著减小了肿瘤大小，并延长了接受或未接受BMP-2治疗的小鼠的生存期。这些结果阐明了miR-656在胶质瘤进展中的作用，并为胶质瘤治疗提供了一个有前景的应用方向。
