1] Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China [2] Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Oncogene. 2015 Jul 30;34(31):4089-97. doi: 10.1038/onc.2014.337. Epub 2014 Oct 20.
Hepatocellular carcinoma (HCC) is one of the leading malignancies worldwide. Myocyte enhancer factor 2C (MEF2C) was traditionally regarded as a development-associated factor and was recently reported to be an oncogene candidate. We have previously reported overexpression of MEF2C in HCC; however, the roles of MEF2C in HCC remain to be clarified. In this study, HCC cell lines and a xenograft mouse model were used to determine the functions of MEF2C in vitro and in vivo, respectively. Specific plasmids and small interfering RNA were used to upregulate and downregulate MEF2C expression, respectively. Functional assays were performed to assess the influence of MEF2C on cell proliferation, and VEGF-induced vasculogenic mimicry, migration/invasion as well as angiogenesis. Co-immunoprecipitation was conducted to identify the interaction of MEF2C and β-catenin. Human HCC tissue microarrays were used to investigate correlations among MEF2C, β-catenin and involved biomarkers. MEF2C was found to mediate VEGF-induced vasculogenic mimicry, angiogenesis and migration/invasion, with involvement of the p38 MAPK and PKC signaling pathways. However, MEF2C itself inhibited tumor growth in vitro and in vivo. MEF2C was upregulated by and directly interacted with β-catenin. The nuclear translocation of β-catenin blocked by MEF2C was responsible for MEF2C-mediated growth inhibition. The nuclear translocation of MEF2C was associated with intracellular calcium signaling induced by β-catenin. HCC microarrays showed correlations of nuclear MEF2C with the angiogenesis-associated biomarker, CD31, and cytosolic MEF2C with the proliferation-associated biomarker, Ki-67. MEF2C showed double-edged activities in HCC, namely mediating VEGF-induced malignancy enhancement while inhibiting cancer proliferation via blockade of Wnt/β-catenin signaling. The overall effect of MEF2C in HCC progression regulation was dictated by its subcellular distribution. This should be determined prior to any MEF2C-associated intervention in HCC.
肝细胞癌（HCC）是全球主要的恶性肿瘤之一。肌细胞增强因子 2C（MEF2C）传统上被认为是一种与发育相关的因子，最近被报道为候选癌基因。我们之前曾报道过 HCC 中 MEF2C 的过表达；然而，MEF2C 在 HCC 中的作用仍有待阐明。在这项研究中，分别使用 HCC 细胞系和异种移植小鼠模型来确定 MEF2C 在体外和体内的功能。使用特定的质粒和小干扰 RNA 分别上调和下调 MEF2C 的表达。进行功能测定以评估 MEF2C 对细胞增殖、VEGF 诱导的血管生成拟态、迁移/侵袭以及血管生成的影响。进行共免疫沉淀以鉴定 MEF2C 和 β-连环蛋白的相互作用。使用人 HCC 组织微阵列来研究 MEF2C、β-连环蛋白和相关生物标志物之间的相关性。发现 MEF2C 介导 VEGF 诱导的血管生成拟态、血管生成和迁移/侵袭，涉及 p38 MAPK 和 PKC 信号通路。然而，MEF2C 本身在体外和体内抑制肿瘤生长。MEF2C 被 β-连环蛋白上调并与其直接相互作用。MEF2C 阻断的 β-连环蛋白核易位是 MEF2C 介导的生长抑制的原因。MEF2C 的核易位与 β-连环蛋白诱导的细胞内钙信号有关。HCC 微阵列显示核 MEF2C 与血管生成相关生物标志物 CD31 相关，细胞质 MEF2C 与增殖相关生物标志物 Ki-67 相关。MEF2C 在 HCC 中具有双重作用，即通过阻断 Wnt/β-连环蛋白信号来介导 VEGF 诱导的恶性增强，同时抑制癌症增殖。MEF2C 在 HCC 进展调控中的总体作用取决于其亚细胞分布。在对 HCC 进行任何 MEF2C 相关干预之前，都应该确定这一点。
