CARF activates beta-catenin/TCF signaling in the hepatocellular carcinoma

Xin Fan; Xiaoyan Ma; Lei Cui; Shengchun Dang; Jianguo Qu; Jianxin Zhang; Xuqing Wang; Zhengfa Mao

doi:10.18632/oncotarget.13138

CARF activates beta-catenin/TCF signaling in the hepatocellular carcinoma

Oncotarget. 2016 Dec 6;7(49):80404-80414. doi: 10.18632/oncotarget.13138.

Authors

Xin Fan¹, Xiaoyan Ma², Lei Cui¹, Shengchun Dang¹, Jianguo Qu¹, Jianxin Zhang¹, Xuqing Wang¹, Zhengfa Mao¹

Affiliations

¹ Department of General Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, PR China.
² Department of Gynecology and Obstetrics, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, PR China.

Abstract

Overactivation of Ras signaling is very common in the hepatocellular carcinoma (HCC) due to its constitutive active mutation, which makes it a big challenge to target Ras signaling. Therefore, identifying effectors downstream of Ras signaling would benefit the development of novel therapeutic strategies. In this study, it was found that the expression of CARF (collaborate of ARF) was induced by oncogenic RasV12. The expression of CARF was up-regulated in both HCC mouse model (Alb-Cre; P53f/f; Loxp-Stop-Loxp-RasG12D) and human HCC clinical samples. Overexpression of CARF promoted the growth and migration of HCC cells, while knocking down the expression of CARF inhibited the growth and migration of HCC cells. In the mechanism study, CARF was found to interact with beta-catenin, impaired the interaction between beta-catenin and ICAT, and activated beta-catenin/TCF signaling. Moreover, knocking down the expression of CARF inhibited the tumorigenesis in the HCC mouse model. Taken together, this study revealed the oncogenic functions of CARF in the tumorigenesis of HCC by activating beta-catenin/TCF signaling, and suggested CARF might be a therapeutic target in the treatment of HCC.

Keywords: CARF; HCC; RasV12; beta-catenin/TCF signaling.

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Gene Expression Regulation, Neoplastic
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Mice, Transgenic
RNA Interference
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*
Signal Transduction
TCF Transcription Factors / genetics
TCF Transcription Factors / metabolism*
Time Factors
Transfection
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
beta Catenin / genetics
beta Catenin / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Apoptosis Regulatory Proteins
CDKN2AIP protein, human
CTNNB1 protein, human
CTNNBIP1 protein, human
Intracellular Signaling Peptides and Proteins
RNA-Binding Proteins
TCF Transcription Factors
TP53 protein, human
Tumor Suppressor Protein p53
beta Catenin
collaborator of ARF protein, mouse