title: Distinct role of interleukin-6 and tumor necrosis factor receptor-1 in oval cell- mediated liver regeneration and inflammation-associated hepatocarcinogenesis.
abstract: Interleukin 6 (IL6), tumor necrosis factor α (TNFα) and TNF receptor-1(TNFR1) have been shown to involve in oval cell proliferation and hepatocellular carcinoma (HCC) development. However, their role in these processes is still unclear. In the present study, by using hepatocytes-specific DDB1 deletion mouse models, we explored the role and mechanism of IL6, TNFα and TNFR1 in oval cell proliferation and HCC development in the context of inflammation, which is the common features of HCC pathogenesis in humans. Our results showed that IL6 promotes oval cell proliferation and liver regeneration, while TNFα/TNFR1 does not affect this process. Deletion of IL6 accelerates HCC development and increases tumor burden. The number of natural killer(NK) cells is significantly decreased in tumors without IL6, implying that IL6 suppresses HCC by NK cells. In contrast to IL6, TNFR1-mediated signaling pathway promotes HCC development, and deletion of TNFR1 reduced tumor incidence. Increased apoptosis, compensatory proliferation and activation of MAPK/MEK/ERK cascade contribute to the oncogenic function of TNFR1-mediated signaling pathway. Intriguingly, deletion of TNFα accelerates tumor development, which shows divergent roles of TNFα and TNFR1 in hepatocarcinogenesis.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, 310058, China.|Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Ji
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D007249:Inflammation / Q000235:genetics*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics*; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008115:Liver Regeneration / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C490415:Ddb1 protein, mouse; D015850:Interleukin-6; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha
keywords: IL6; NK cell; TNFR1; hepatocellular carcinoma; oval cell