School of Life Science and Biotechnology, Harbin Institute of Technology, Harbin, Heilongjiang, China.
Cancer Sci. 2012 Apr;103(4):716-22. doi: 10.1111/j.1349-7006.2012.02220.x. Epub 2012 Mar 8.
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.
我们之前发现 MARVELD1 的表达在多种肿瘤组织中显著下调，但在肝细胞癌（HCC）中尚不清楚，其功能尚未被探索。在本研究中，为了揭示 MARVELD1 在 HCC 发病机制和发展中的潜在机制，我们研究了 MARVELD1 的表达模式及其对 HCC 肿瘤增殖的影响。结果表明，MARVELD1 在 HCC 的临床样本和细胞系中的频繁下调是由于启动子甲基化和遗传缺失所致。此外，用去甲基化剂 5-氮杂-2'-脱氧胞苷处理 MARVELD1 不表达的 Hep3B2.1-7 和 PLC/PRF/5 细胞可恢复其表达。MARVELD1 的过表达在体外和体内抑制 HCC 细胞的增殖，而 shRNAs 下调内源性 MARVELD1 则显著增强了这些特征。MARVELD1 的过表达可增强 HCC 细胞对表柔比星和 10-羟基喜树碱的化疗敏感性。相应的结果是，在 MARVELD1 转染细胞中，p-ERK1/2 和 cyclin D1 的表达降低，而 p16 和 p53 的表达增加。我们还证明，MARVELD1 的敲低导致 p-ERK1/2 和 cyclin D1 的上调，以及 p16 和 p53 的下调。此外，当 MARVELD1 过表达细胞转染 p53 或 p16 siRNA 时，细胞生长速度降低的影响显著逆转。我们的研究结果表明，MARVELD1 是一种肿瘤抑制因子，通过在体外和体内增加 p53 和 p16，负调控 HCC 细胞的增殖、肿瘤生长和化疗敏感性。MARVELD1 可能是 HCC 治疗的一个潜在靶点。
