β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

Yidong Yang; Yunwei Guo; Siwei Tan; Bilun Ke; Jin Tao; Huiling Liu; Jie Jiang; Jianning Chen; Guihua Chen; Bin Wu

doi:10.1038/ncomms8369

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

Nat Commun. 2015 Jun 16:6:7369. doi: 10.1038/ncomms8369.

Authors

Yidong Yang¹, Yunwei Guo¹, Siwei Tan¹, Bilun Ke¹, Jin Tao¹, Huiling Liu¹, Jie Jiang¹, Jianning Chen², Guihua Chen³, Bin Wu¹

Affiliations

¹ 1] Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510630, China [2] Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, 510630, China.
² Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510630, China.
³ 1] Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, 510630, China [2] Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510630, China.

PMID: 26077142
DOI: 10.1038/ncomms8369

Abstract

G-protein-coupled receptors (GPCR) constitute the largest known superfamily for signal transduction and transmission, and they control a variety of physiological and pathological processes. GPCR adaptor β-arrestins (ARRBs) play a role in cancerous proliferation. However, the effect of ARRBs in inflammation-mediated hepatocellular carcinogenesis is unknown. Here we show that ARRB1, but not ARRB2, is upregulated in inflammation-associated hepatocellular carcinoma (HCC) and paracancerous tissues in humans. A genotoxic carcinogen, diethylnitrosamine (DEN), significantly induces hepatic inflammation, TNF-α production and ARRB1 expression. Although ARRB1 deficiency does not affect hepatic inflammation and TNF-α production, it markedly represses hepatocellular carcinogenesis by suppressing malignant proliferation in DEN-treated mice. Furthermore, TNF-α directly induces hepatic ARRB1 expression and enhances ARRB1 interaction with Akt by binding to boost Akt phosphorylation, resulting in malignant proliferation of liver cells. Our data suggest that ARRB1 enhances hepatocellular carcinogenesis by inflammation-mediated Akt signalling and that ARRB1 may be a potential therapeutic target for HCC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkylating Agents / toxicity
Animals
Arrestins / drug effects
Arrestins / genetics*
Arrestins / metabolism
Blotting, Western
Carcinogenesis / genetics*
Carcinogenesis / immunology
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / immunology
Cell Line, Tumor
Diethylnitrosamine / toxicity
Hep G2 Cells
Humans
Immunohistochemistry
Inflammation
Liver Neoplasms / genetics*
Liver Neoplasms / immunology
Liver Neoplasms / pathology
Liver Neoplasms, Experimental / chemically induced
Liver Neoplasms, Experimental / genetics*
Liver Neoplasms, Experimental / immunology
Liver Neoplasms, Experimental / pathology
Magnetic Resonance Imaging
Mice
Mice, Knockout
Neoplasm Transplantation
Proto-Oncogene Proteins c-akt / immunology
Proto-Oncogene Proteins c-akt / metabolism*
RNA, Messenger / metabolism*
Real-Time Polymerase Chain Reaction
Signal Transduction
Tumor Necrosis Factor-alpha / immunology
beta-Arrestin 1
beta-Arrestin 2
beta-Arrestins

Substances

ARRB1 protein, human
ARRB2 protein, human
Alkylating Agents
Arrb1 protein, mouse
Arrb2 protein, mouse
Arrestins
RNA, Messenger
Tumor Necrosis Factor-alpha
beta-Arrestin 1
beta-Arrestin 2
beta-Arrestins
Diethylnitrosamine
Proto-Oncogene Proteins c-akt