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 epithelial-mesenchymal 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.
Highlights
Deaths resulting from hepatocellular carcinoma (HCC) rank third in all malignancy-related mortality [1]
Univariate analysis demonstrated that tumor diameter, differentiation, and CR6-interacting factor 1 (CRIF1) expression were of statistical significance
We found increased expression of TGF-β receptor I, Smad2, Smad3, phosphorylated Smad2 (p-Smad2) and phosphorylated Smad3 (p-Smad3) (Figure 4E), indicating activation of TGF-β/Smad signaling in CRIF1 suppressed HCC cells
Summary
Deaths resulting from hepatocellular carcinoma (HCC) rank third in all malignancy-related mortality [1]. Surgical resection and liver transplantation are the best options for HCC treatment. Majority of HCC patients are not eligible for surgical operation due to metastasis, which is a major obstacle to cure. Systemic dissection of the molecular mechanisms underlying metastatic progression of HCC is necessary for the development of new diagnostic and therapeutic strategies to prevent and treat metastases. CR6-interacting factor 1 (CRIF1), known as Gadd45gip or PRG6, regulates cell cycle by inhibiting G1 to S phase progression, and binds to Gadd family [5], which plays an important role in genomic stability and regulation of the cell cycle. The precise role of CRIF1 in HCC has not been investigated
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