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Cancer Res. 2014 Sep 15;74(18):5287-300. doi: 10.1158/0008-5472.CAN-14-0284. Epub 2014 Jul 23.

Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying β-catenin degradation.

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  • 1Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China.
  • 2Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 3Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China.
  • 4Department of Digestion, Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 5Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China. shao5022@163.com Hongkui88@163.com.
  • 6Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China. Jiangxi Province Engineering Research Center of Hepatobiliary Disease, Nanchang, China. Jiangxi Province Key Laboratory of Molecular Medicine, Nanchang, China. shao5022@163.com Hongkui88@163.com.

Abstract

The ubiquitin-like protein FAT10 and the homeobox protein HOXB9 each promote metastatic progression in hepatocellular carcinoma (HCC). In this study, we investigated the clinicopathologic significance of FAT10 and HOXB9 in HCC and investigated a mechanistic role for FAT10 in HOXB9-mediated invasiveness and metastasis. Relative to adjacent normal tissues, FAT10 and HOXB9 were markedly overexpressed in HCC, where a positive correlation in their expression and associated malignant characteristics were found. RNAi-mediated silencing of FAT10 decreased HOXB9 expression and inhibited HCC invasion and metastasis in vitro and in vivo. The effects of FAT10 silencing were reversed by HOXB9 overexpression, whereas RNAi-mediated silencing of HOXB9 decreased HCC invasion and metastasis driven by FAT10 overexpression. Mechanistically, FAT10 regulated HOXB9 expression by modulating the β-catenin/TCF4 pathway, directly binding to β-catenin and preventing its ubiquitination and degradation. Together, our results identified a novel HCC regulatory circuit involving FAT10, β-catenin/TCF4, and HOXB9, the dysfunction of which drives invasive and metastatic character in HCC. Cancer Res; 74(18); 5287-300. ©2014 AACR.

PMID:
25056121
DOI:
10.1158/0008-5472.CAN-14-0284
[PubMed - indexed for MEDLINE]
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