title: MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry.
abstract: Invasion and metastasis is the main causes leading to the death of hepatocellular carcinoma (HCC) patients. However, the underlying mechanism is still to be explored. Transforming growth factor β1 (TGF-β1) is a stronger inducer of HCC cell invasion. However, the downstream effector of TGF-β1 that promotes HCC invasion is still unknown. In this study, we found that PI3K/Akt activation takes place following the stimulation of TGF-β1. The inhibition of PI3K/Akt activation abolished epithelial-mesenchymal transition (EMT) and invasion of HCC cells induced by TGF-β1. Myocyte enhancer factors 2 (MEF2) family proteins were found to be overexpressed in HCC cells under the treatment of TGF-β1 in a PI3K/Akt-dependent way. Silencing the expression of MEF2s was able to prevent the effect of TGF-β1 on HCC EMT and invasion. Unexpectedly, MEF2 proteins were able to promote the expression of TGF-β1 in HCC cells, suggesting the existence of regulatory circuitry consisting of TGF-β1, PI3K/Akt, and MEF2. A natural compound, oleanolic acid, was demonstrated to suppress the invasion and EMT of HCC cells by downregulating MEF2, showing that targeting this pathway is an effective therapeutic strategy for HCC invasion. We believe that our findings can contribute to better understanding of the involved mechanism of HCC invasion and the development of preventive and therapeutic strategy.
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, 127 Dongming Road, 450008, Zhengzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: Changshan
authors.initials: C
authors.lastname: Huang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Yuechao
authors.initials: Y
authors.lastname: Ding
authors.forename: Chao
authors.initials: C
authors.lastname: Ma
authors.forename: Hongbo
authors.initials: H
authors.lastname: Ma
authors.forename: Weiyu
authors.initials: W
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009828:Oleanolic Acid / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D064326:MEF2 Transcription Factors; D009828:Oleanolic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1
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