MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma
MARVELD1 inhibited cell proliferation and enhance chemosensitivity via increasing expression of p53 and p16 in hepatocellular carcinoma
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MARVELD1 通过增加肝细胞癌中 p53 和 p16 的表达来抑制细胞增殖并增强化疗敏感性
DOI：
10.1111/j.1349-7006.2012.02220.x
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发表时间：
2012-04-01
期刊：
影响因子：
5.7
通讯作者：
Li, Yu
中科院分区：
文献类型：
--
作者：
Yu, Youtao;Zhang, Yubao;Li, Yu
我们已经发现MARVELD1在多种肿瘤组织中的表达显著下调，但在肝细胞癌中的表达尚不清楚，其功能尚未被研究。本研究旨在探讨MARVELD1在肝细胞癌发生发展中的作用机制，探讨MARVELD1在肝细胞癌中的表达模式及其对肿瘤增殖的影响。结果表明，临床标本和肝癌细胞系中MARVELD1基因的表达频繁下调是由于启动子甲基化和基因缺失所致。此外，MARVELD1不表达的Hep3B2.1-7和PLC/PRF/5细胞用去甲基化试剂5-aza-2‘脱氧胞苷处理后恢复其表达。在体内外，MARVELD1过表达抑制了肝癌细胞的增殖，而shRNAs下调内源性MARVELD1则显著增强了这些特性。MARVELD1过表达可增强肝癌细胞对表阿霉素和10-羟基喜树碱的化疗敏感性。与此相对应，MARVELD1转染组p-ERK1/2和细胞周期蛋白D1表达降低，而p16和p53表达增加。我们还发现，MARVELD1基因敲除后，p-ERK1/2和细胞周期蛋白D1表达上调，p16和p53表达下调。此外，将p53或p16 siRNA导入MARVELD1过表达细胞后，细胞生长速度下降的影响被显著逆转。我们的研究结果表明，MARVELD1在体内外通过上调p53和p16的表达，负向调节肝癌细胞的增殖、肿瘤生长和化疗敏感性，从而发挥肿瘤抑制作用。MARVELD1可能成为肝癌治疗的潜在靶点。(《癌症科学》2012；103：716-722)
We have previously found that expression of MARVELD1 was remarkably downregulated in multiple tumor tissues, but unclear in hepatocellular carcinoma (HCC) and its function has not been explored yet. In the present study, to uncover the underlying mechanism of MARVELD1 in the pathogenesis and development of HCC, we investigated the expression pattern of MARVELD1 and its effect on tumor proliferation in HCC. The results indicated the frequent downregulation of MARVELD1 in clinic samples and cell lines of HCC resulted from promoter methylation, as well as genetic deletion. Furthermore, treatment of MARVELD1 unexpressing Hep3B2.1‐7 and PLC/PRF/5 cells with the demethylating agent 5‐aza‐2′ deoxycytidine restored its expression. Overexpression of MARVELD1 suppressed the proliferation of HCC cells in vitro and in vivo, whereas downregulation of endogenous MARVELD1 by shRNAs significantly enhanced these characters. MARVELD1 overexpression could enhance chemosensitivity of HCC cells to epirubicin and 10‐hydroxycamptothecin. Corresponding to these results, the expression of p‐ERK1/2 and cyclin D1 were decreased, whereas p16 and p53 were increased in MARVELD1‐transfected cells. We also demonstrated that knockdown of MARVELD1 resulted in upregulation of p‐ERK1/2 and cyclin D1, and downregulation of p16 and p53. Moreover, the effect of the decreased cell growth rate was significantly reversed when MARVELD1‐overexpressing cells were trasfected with p53 or p16 siRNA. Our findings suggest that MARVELD1 is a tumor suppressor by negatively regulating proliferation, tumor growth and chemosensitivity of HCC cells via increasing p53 and p16 in vitro and in vivo. MARVELD1 may be a potential target for HCC therapy. (Cancer Sci 2012; 103: 716–722)