title: β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling.
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.
authors.affiliation: 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.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Siwei
authors.initials: S
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Bilun
authors.initials: B
authors.lastname: Ke
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: Huiling
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510630, China.
authors.forename: Jianning
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Bin
authors.identifier: 000000023284908X
authors.initials: B
authors.lastname: Wu
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D019390:Arrestins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics* / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D004052:Diethylnitrosamine / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; D000477:Alkylating Agents; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D004052:Diethylnitrosamine; D051057:Proto-Oncogene Proteins c-akt