Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-09, Vol.81 (18), p.4766-4777
• Main Authors: Shriki, Anat, Lanton, Tali, Sonnenblick, Amir, Levkovitch-Siany, Orr, Eidelshtein, Dana, Abramovitch, Rinat, Rosenberg, Nofar, Pappo, Orit, Elgavish, Sharona, Nevo, Yuval, Safadi, Rifaat, Peled, Amnon, Rose-John, Stefan, Galun, Eithan, Axelrod, Jonathan H
• Format: Article
• Language: English
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding Cassette Sub-Family B Member 4; Biomarkers; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cellular Senescence - genetics; Disease Models, Animal; Disease Progression; Fatty Liver - etiology; Fatty Liver - metabolism; Fatty Liver - pathology; Female; Immunohistochemistry; Interleukin-6 - genetics; Interleukin-6 - metabolism; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Knockout; Mice, Transgenic
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-21-0321

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 senescence-associated 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 NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development. .