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 () and Bin Wu ()
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Yidong Yang: The Third Affiliated Hospital of Sun Yat-Sen University
Yunwei Guo: The Third Affiliated Hospital of Sun Yat-Sen University
Siwei Tan: The Third Affiliated Hospital of Sun Yat-Sen University
Bilun Ke: The Third Affiliated Hospital of Sun Yat-Sen University
Jin Tao: The Third Affiliated Hospital of Sun Yat-Sen University
Huiling Liu: The Third Affiliated Hospital of Sun Yat-Sen University
Jie Jiang: The Third Affiliated Hospital of Sun Yat-Sen University
Jianning Chen: The Third Affiliated Hospital of Sun Yat-Sen University
Guihua Chen: Guangdong Provincial Key Laboratory of Liver Disease Research
Bin Wu: The Third Affiliated Hospital of Sun Yat-Sen University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8369

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