Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis
| Autor: | Orr Levkovitch-Siany, Anat Shriki, Rifaat Safadi, Sharona Elgavish, Amir Sonnenblick, Yuval Nevo, Rinat Abramovitch, Jonathan H. Axelrod, Amnon Peled, Orit Pappo, Eithan Galun, Nofar Rosenberg, Stefan Rose-John, Dana Eidelshtein, Tali Lanton |
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| Rok vydání: | 2021 |
| Předmět: |
Senescence
Cancer Research ATP Binding Cassette Transporter Subfamily B Mice Transgenic medicine.disease_cause Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine medicine Animals STAT3 Cellular Senescence 030304 developmental biology Mice Knockout Liver injury 0303 health sciences biology Interleukin-6 Liver Neoplasms medicine.disease Immunohistochemistry 3. Good health Fatty Liver Disease Models Animal Cell Transformation Neoplastic Oncology Hepatocellular carcinoma Disease Progression biology.protein Cancer research Female 030211 gastroenterology & hepatology Steatosis Liver cancer Carcinogenesis Biomarkers |
| Zdroj: | Cancer Research |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. See related commentary by Huynh and Ernst, p. 4671 |
| Databáze: | OpenAIRE |
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