CR6-interacting factor 1 inhibits invasiveness by suppressing TGF- β-mediated epithelial-mesenchymal transition in hepatocellular carcinoma

Abstract

CR6-interacting factor 1 (CRIF1) regulates cell cycle progression and the DNA damage response. Here, we show that CRIF1 expression is decreased in hepatocellular carcinoma (HCC) tissues and positively correlates with patients' survival. In vitro, down-regulation of CRIF1 promotes HCC cell proliferation and invasiveness, while over-expression has the opposite effect. in vivo, CRIF1 knockdown enhances growth of HCC xenografts. Analysis of mRNA microarrays showed that CRIF1 knockdown activates genes involved in TGF-β RI/Smad2/3 signaling, leading to epithelialmesenchymal transition (EMT) and increased matrix metalloproteinase-3 (MMP3) expression. However, cell invasion and EMT are abrogated in HCC cells treated with SB525334, a specific TGF-β RI inhibitor, which indicates the inhibitory effect of CRIF1 on HCC tumor growth is mediated by TGF-β signaling. These results demonstrate that CRIF1 benefits patient survival by inhibiting HCC cell invasiveness through suppression of TGF-β-mediated EMT and MMP3 expression. This suggests CRIF1 may serve as a novel target for inhibiting HCC metastasis.