Myocyte enhancer factor 2C regulation of hepatocellular carcinoma via vascular endothelial growth factor and Wnt/β-catenin signaling

• Published in: Oncogene Vol. 34; no. 31; pp. 4089 - 4097
• Main Authors: Bai, X L, Zhang, Q, Ye, L Y, Liang, F, Sun, X, Chen, Y, Hu, Q D, Fu, Q H, Su, W, Chen, Z, Zhuang, Z P, Liang, T B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.07.2015; Nature Publishing Group
• Subjects: 14/105; 14/19; 631/67/1504/1610; 82; 82/1; 96/109; 96/21; Angiogenesis; Animals; Apoptosis; beta Catenin - metabolism; Biomarkers; Calcium (intracellular); Calcium signalling; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell proliferation; Cell Proliferation - genetics; Disease Progression; Genetic aspects; Hepatocellular carcinoma; Hepatoma; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Intracellular signalling; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Malignancy; MAP kinase; Medicine; Medicine & Public Health; MEF2 Transcription Factors - metabolism; MEF2 Transcription Factors - physiology; Mice; Mice, Inbred BALB C; Mice, Nude; Mimicry; Nuclear transport; Oncology; original-article; Plasmids; Protein kinase C; siRNA; Tissue Distribution; Tumor Cells, Cultured; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - physiology; Wnt protein; Wnt proteins; Wnt Signaling Pathway - physiology; Xenografts; β-Catenin; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.337

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.