The Activation of MEK/ERK Signaling Pathway by Bone Morphogenetic Protein 4 to Increase Hepatocellular Carcinoma Cell Proliferation and Migration
The Activation of MEK/ERK Signaling Pathway by Bone Morphogenetic Protein 4 to Increase Hepatocellular Carcinoma Cell Proliferation and Migration
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DOI：
10.1158/1541-7786.mcr-11-0293
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发表时间：
2012-03-01
影响因子：
5.2
通讯作者：
Cheng, Kuang-Hung
中科院分区：
文献类型：
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作者：
Chiu, Chiang-Yen;Kuo, Kung-Kai;Cheng, Kuang-Hung
肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内最常见的恶性肿瘤之一，发病率高，预后差。骨形态发生蛋白4（BMP 4）属于TGF-β超家族蛋白质，是一种多功能细胞因子，其通过SMAD依赖性和非SMAD依赖性途径发挥其生物学作用，并且还已知参与人类致癌作用。然而，BMP 4信号在肝癌发生中的作用尚未明确。在这里，我们首先表明，BMP 4及其受体，BMPR 1A，在大多数原发性肝癌过表达，并在体外促进肝癌细胞系的生长和迁移。我们还确定BMP 4可以诱导肝癌细胞周期蛋白依赖性激酶（CDK）1和细胞周期蛋白B1上调，以加速细胞周期进程。我们的研究表明，肝癌细胞增殖的诱导是独立的SMAD信号通路，因为肝癌细胞系的Smad 4敲低仍然导致BMP 4处理后的CDK 1和细胞周期蛋白B1的表达上调。使用丝裂原活化蛋白/细胞外信号调节激酶（MEK）选择性抑制剂，CDK 1、细胞周期蛋白B1 mRNA和蛋白的诱导显示依赖于MEK/细胞外信号调节激酶（ERK）信号通路的激活。体内异种移植研究证实，BMPR 1A敲低细胞的致瘤性显著低于对照组。我们的研究结果表明，在HCC中BMP 4和BMPR 1A的上调促进HCC细胞的增殖和转移，并且CDK 1和cyclin B1是HCC肿瘤发生过程中BMP 4信号通路中重要的SMAD非依赖性分子靶点。提示BMP 4信号通路可能成为肝癌治疗的新靶点。Mol Cancer Res; 10（3）; 415-27.（C）2012年AACR。
Hepatocellular carcinoma (HCC) is one of the most common visceral malignancies worldwide, with a very high incidence and poor prognosis. Bone morphogenesis protein 4 (BMP4), which belongs to the TGF-beta superfamily of proteins, is a multifunctional cytokine, which exerts its biologic effects through SMAD- and non-SMAD-dependent pathways, and is also known to be involved in human carcinogenesis. However, the effects of the BMP4 signaling in liver carcinogenesis are not yet clearly defined. Here, we first show that BMP4 and its receptor, BMPR1A, are overexpressed in a majority of primary HCCs and that it promotes the growth and migration of HCC cell lines in vitro. We also establish that BMP4 can induce HCC cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression. Our study indicates that the induction of HCC cell proliferation is independent of the SMAD signaling pathway, as Smad4 knockdown of HCC cell lines still leads to the upregulation of CDK1 and cyclin B1 expression after BMP4 treatment. Using mitogen-activated protein/extracellular signal-regulated kinase (MEK) selective inhibitors, the induction of CDK1, cyclin B1 mRNA and protein were shown to be dependent on the activation of MEK/extracellular signal-regulated kinase (ERK) signaling. In vivo xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than the control groups. Our findings show that the upregulation of BMP4 and BMPR1A in HCC promotes the proliferation and metastasis of HCC cells and that CDK1 and cyclin B1 are important SMAD-independent molecular targets in BMP4 signaling pathways, during the HCC tumorigenesis. It is proposed that BMP4 signaling pathways may have potential as new therapeutic targets in HCC treatment. Mol Cancer Res; 10(3); 415-27. (C)2012 AACR.