Genistein inhibits hepatocellular carcinoma cell migration by reversing the epithelial-mesenchymal transition: partial mediation by the transcription factor NFAT1.
To investigate the effects and mechanism of genistein on hepatocellular carcinoma. Cell counting kit-8 assays showed that genistein at 3, 6, and 9 µM had no significant cytotoxic effects on HepG2, SMMC-7721, and Bel-7402 cells. Cell scratch and Transwell assays identified that genistein inhibited migration of three cell lines. In three cell lines, genistein enhanced E-cadherin and α-catenin, but reduced N-cadherin and Vimentin at both mRNA and protein levels in a dose-dependent manner. Simultaneously, treatment with genistein suppressed epithelial-mesenchymal transition (EMT) induced by TGF-β. In HepG2 cells, genistein reduced mRNA, and protein expressions of nuclear factor of activated T cells 1 (NFAT1), Abca3, Autotaxin, CD154, and Cox-2. Phorbol 12-myristate 13-acetate (PMA) and ionomycin enhanced activity of NFAT1, reduced E-cadherin and α-catenin protein levels, and increased protein levels of N-cadherin and Vimentin. Transwell demonstrated that PMA and ionomycin reversed the migration inhibitory effects of genistein on HepG2 cells. In vivo, genistein inhibited the intrahepatic metastasis by reversing the EMT, which was correlated with reduced NFAT1 . Genistein inhibited hepatocellular carcinoma cell migration by reversing the EMT, which was partly mediated by NFAT1. The fact that EMT can be reversed by genistein may shed light on the possible mechanisms for its role in liver cancer therapy.
Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China.
Weiqi
W
Dai
Fan
F
Wang
Lei
L
He
Chunlei
C
Lin
Shumei
S
Wu
Ping
P
Chen
Yan
Y
Zhang
Miao
M
Shen
Dong
D
Wu
Chengfen
C
Wang
Jie
J
Lu
Yingqun
Y
Zhou
Xuanfu
X
Xu
Ling
L
Xu
Chuanyong
C
Guo
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000627:therapeutic use*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000032:analysis / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics
D016588:Anticarcinogenic Agents; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D019833:Genistein
epithelial-mesenchymal tlransition; genistein; hepatocellular carcinoma; migration