CR6-interacting factor 1 inhibits invasiveness by suppressing TGF-β-mediated epithelial-mesenchymal transition in hepatocellular carcinoma
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Runzhou Zhuang1,3,*, Di Lu1,2,3,*, Jianyong Zhuo1,3, Xuanyu Zhang1,3, Kun Wang1,3, Xuyong Wei1,2,3, Qiang Wei1,2,3, Wei Wang1,3, Haiyang Xie1,3, Lin Zhou1,3, Xiao Xu1,2,3 and Shusen Zheng1,2,3
1Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
2Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
3Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
*These authors have contributed equally to this work
Xiao Xu, email: firstname.lastname@example.org
Shusen Zheng, email: email@example.com
Keywords: CR6-interacting factor 1; hepatocellular carcinoma; TGF-β; EMT
Received: May 13, 2017 Accepted: August 09, 2017 Published: October 19, 2017
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.
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