Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescenceassociated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASHassociated phenotypes and by reinforcing the antitumorigenic effects of the SASP.
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The authors are grateful to Deborah Olam for excellent technical assistance, to Neta Barashi for helpful discussions and advice, to Tali Bdolah-Abram for expert advice on statistical evaluations, and to the Core Research Facility (CRF) and staff members at The Faculty of Medicine, the Hebrew University of Jerusalem. J.H. Axelrod was supported by grants to from the Israel Science Foundation (ISF 923/14) and the Israel Cancer Research Fund (8004906). The work of E. Galun was supported by grants from the ISF collaboration with Canada (2473/2017), the personal ISF (486/2017) and the ISF and ICORE (ISF 41/2011), the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841), and the ERC advance - GA number 786575 – RxmiRcanceR (to E. Galun) and the Israel Ministry of Science and Technology (MOST). The work of E. Galun was also supported by the Kron, Raskin, and Robert Benson foundations. The work of S. Rose-John was supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB877, Project A1; SFB841, Project C1) and by the Cluster of Excellence “Inflammation at Interfaces.” A. Sonnenblick was supported by grants from the Kass Research Award-American Physicians Fellowship for Medicine in Israel, the Israel Cancer Association, Israel
Cancer Research Foundation Fellowship, Hadassah Medical Center Internal Grant, and the Morasha Program of the Israel Science Foundation grant (ISF1728/11).
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