Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of human cancers for which there is currently no satisfactory treatment.[1]
Considering the potent pro-tumor effects of Vascular endothelial growth factor (VEGF) and the validity of VEGF-targeted therapy in cancer,[18] we first investigated whether Myocyte enhancer factor 2C (MEF2C)-mediated VEGF signaling in HCC cells as it does in endothelial cells.[8,10]
Compared with non-inhibited controls, the upregulation of phosphorylated MEF2C (p-MEF2C) induced by VEGF was attenuated in both cell lines by the PKC and p38 MAPK inhibitors, whereas inhibition of JNK and ERK1/2 signaling affected only Sk-hep-1 cells and inhibition of PI3K showed no influence on both cell lines (Figure 1d)
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of human cancers for which there is currently no satisfactory treatment.[1] the mechanisms of initiation and progression of HCC have been widely studied for decades, the details of these processes remain to be elucidated. Myocyte enhancer factor 2C (MEF2C) is a member of the MEF2 family, which is known to be a central regulator of cell differentiation and organogenesis.[2] MEF2C is a co-transcription factor, and was previously thought to be predominantly involved in the differentiation of myocytes, endothelial cells, neurons, lymphocytes, chondrocytes and neural crest cells.[2] Recently, the oncogenic role of MEF2C has been revealed. Previous studies implicated MEF2C as a potential oncogene in leukemia, colon cancer and pancreatic cancer.[3,4,5]
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