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Cited by 34Liver physiology and pathologyCytokine Signaling Pathways and InteractionsHepatocellular Carcinoma Treatment and Prognosis

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

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Shriki, Anat, Lanton, Tali, Sonnenblick, Amir, Levkovitch-Siany, Orr, Eidelshtein, Dana, Abramovitch, Rinat, Rosenberg, Nofar, Pappo, Orit +7 more·2021·Cancer Research
DOI 10.1158/0008-5472.can-21-0321

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Abstract

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

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  • In mdr2−/− mice, deletion of il6 or blockade of IL-6 trans-signaling by soluble gp130 exacerbates hepatic steatosis, inflammation, chronic hepatitis, and hepatocarcinogenesis, suggesting a protective role of IL-6 signaling.

    “In the mdr2−/− mouse model, the deletion of il6 gene or blockade of IL-6 trans-signaling by the soluble gp130 form exacerbated hepatic steatosis, inflammation, chronic hepatitis, and hepatocarcinogenesis, suggesting the protective role of IL-6 signaling [74].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [74]

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Research works printed but not linked: 45

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
  2. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127:S35-50.
  3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
  4. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461-6.
  5. He G, Karin M. NF-kappaB and STAT3 -key players in liver inflammation and cancer. Cell Res 2011;21:159-68.
  6. Barashi N, Weiss ID, Wald O, Wald H, Beider K, Abraham M, et al. Inflam- mation-induced hepatocellular carcinoma is dependent on CCR5 in mice. Hepatology 2013;58:1021-30.
  7. Carloni V, Luong TV, Rombouts K. Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever. Liver Int 2014; 34:834-43.
  8. Coulouarn C, Clement B. Stellate cells and the development of liver cancer: therapeutic potential of targeting the stroma. J Hepatol 2014;60:1306-9.
  9. Brunt EM, Wong VW, Nobili V, Day CP, Sookoian S, Maher JJ, et al. Nonal- coholic fatty liver disease. Nat Rev Dis Primers 2015;1:15080.
  10. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317:121-4.
  11. Feng GS. Conflicting roles of molecules in hepatocarcinogenesis: paradigm or paradox. Cancer Cell 2012;21:150-4.
  12. Abiru S, Migita K, Maeda Y, Daikoku M, Ito M, Ohata K, et al. Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepa- titis. Liver Int 2006;26:39-45.
  13. Kakumu S, Shinagawa T, Ishikawa T, Yoshioka K, Wakita T, Ito Y, et al. Serum interleukin 6 levels in patients with chronic hepatitis B. Am J Gastroenterol 1991; 86:1804-8.
  14. Malaguarnera M, Di Fazio I, Laurino A, Ferlito L, Romano M, Trovato BA. Serum interleukin 6 concentrations in chronic hepatitis C patients before and after interferon-alpha treatment. Int J Clin Pharmacol Ther 1997;35:385-8.
  15. Porta C, De Amici M, Quaglini S, Paglino C, Tagliani F, Boncimino A, et al. Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma. Ann Oncol 2008;19:353-8.
  16. Lanton T, Shriki A, Nechemia-Arbely Y, Abramovitch R, Levkovitch O, Adar R, et al. Interleukin 6-dependent genomic instability heralds accelerated carcino- genesis following liver regeneration on a background of chronic hepatitis. Hepatology 2017;65:1600-11.
  17. Demetris AJ, Lunz JG 3rd, Specht S, Nozaki I. Biliary wound healing, ductular reactions, and IL-6/gp130 signaling in the development of liver disease. World J Gastroenterol 2006;12:3512-22.
  18. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002;8:75-9.
  19. Zuliani G, Galvani M, Maggio M, Volpato S, Bandinelli S, Corsi AM, et al. Plasma soluble gp130 levels are increased in older subjects with metabolic syndrome. The role of insulin resistance. Atherosclerosis 2010;213:319-24.
  20. Mauad TH, van Nieuwkerk CM, Dingemans KP, Smit JJ, Schinkel AH, Noten- boom RG, et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 1994;145:1237-45.
  21. Aravinthan AD, Alexander GJM. Senescence in chronic liver disease: is the future in aging? J Hepatol 2016;65:825-34.
  22. Barash H, RG E, Edrei Y, Ella E, Israel A, Cohen I, et al. Accelerated carcino- genesis following liver regeneration is associated with chronic inflammation- induced double-strand DNA breaks. Proc Natl Acad Sci U S A 2010;107: 2207-12.
  23. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003;22:5093-107.
  24. Wendum D, Barbu V, Rosmorduc O, Arrive L, Flejou JF, Poupon R. Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. Virchows Arch 2012;460:291-8.
  25. Rabe B, Chalaris A, May U, Waetzig GH, Seegert D, Williams AS, et al. Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood 2008;111:1021-8.
  26. Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 1999;274:305-15.
  27. Nechemia-Arbely Y, Barkan D, Pizov G, Shriki A, Rose-John S, Galun E, et al. IL- 6/IL-6R axis plays a critical role in acute kidney injury. J Am Soc Nephrol 2008; 19:1106-15.
  28. Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004;127:261-74.
  29. Mair M, Zollner G, Schneller D, Musteanu M, Fickert P, Gumhold J, et al. Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis. Gastroenterology 2010; 138:2499-508.
  30. Potikha T, Stoyanov E, Pappo O, Frolov A, Mizrahi L, Olam D, et al. Interstrain differences in chronic hepatitis and tumor development in a murine model of inflammation-mediated hepatocarcinogenesis. Hepatology 2013;58:192-204.
  31. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 2006;80:227-36.
  32. Tenhumberg S, Waetzig GH, Chalaris A, Rabe B, Seegert D, Scheller J, et al. Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130. J Biol Chem 2008;283:27200-7.
  33. Bergmann J, Muller M, Baumann N, Reichert M, Heneweer C, Bolik J, et al. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology 2017;65:89-103.
  34. Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metab- olism in vivo. Nat Med 2004;10:168-74.
  35. Hefetz-Sela S, Stein I, Klieger Y, Porat R, Sade-Feldman M, Zreik F, et al. Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-Jun phosphorylation. Proc Natl Acad Sci U S A 2014;111: 17582-7.
  36. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132:2328-39.
  37. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflam- matory network. Cell 2008;133:1019-31.
  38. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer devel- opment. Nature 2011;479:547-51.
  39. He S, Sharpless NE. Senescence in health and disease. Cell 2017;169:1000-11.
  40. Pencik J, Schlederer M, Gruber W, Unger C, Walker SM, Chalaris A, et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat Commun 2015;6:7736.
  41. Ferreira-Gonzalez S, Lu WY, Raven A, Dwyer B, Man TY, O'Duibhir E, et al. Paracrine cellular senescence exacerbates biliary injury and impairs regenera- tion. Nat Commun 2018;9:1020.
  42. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006;43: S45-53.
  43. Date M, Matsuzaki K, Matsushita M, Sakitani K, Shibano K, Okajima A, et al. Differential expression of transforming growth factor-beta and its receptors in hepatocytes and nonparenchymal cells of rat liver after CCl4 administration. J Hepatol 1998;28:572-81.
  44. Nechemia-Arbely Y, Shriki A, Denz U, Drucker C, Scheller J, Raub J, et al. Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation. J Hepatol 2011;54:922-9.
  45. Payne CM, Bernstein C, Dvorak K, Bernstein H. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. Clin Exp Gastroenterol 2008;1:19-47.

Cited by

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Authors
Shriki, A., Lanton, T., Sonnenblick, A., Levkovitch-Siany, O., Eidelshtein, D., Abramovitch, R., Rosenberg, N., Pappo, O., Elgavish, S., Nevo, Y., Safadi, R., Peled, A., Rose-John, S., Galun, E., & Axelrod, J. H.
Affiliations
  • Hadassah Medical Center (IL)
  • Tel Aviv University (IL)
  • 1Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
  • Hebrew University of Jerusalem (IL)
  • 8Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
Corresponding author
  • Galun, Eithan
  • Axelrod, Jonathan H.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2021-06-11
Volume
81
Issue
18
Pages
4766-4777
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-21-0321
OpenAlex
W3168168939
Cited by
34
References
10
Citations by year
2026: 9 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 1
FWCI
2.64
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Israel Science Foundation (ISF 923/14, ISF1728/11)
  • Israel Cancer Research Fund (8004906)
  • ISF (2473/2017, 486/2017)
  • ISF ICORE (ISF 41/2011)
  • Deutsche Forschungsgemeinschaft (SFB841, SFB877)
  • ERC (786575, SFB877)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
interleukin-6, STAT3 signaling, hepatocellular carcinoma, chronic hepatitis, hepatocarcinogenesis, nonalcoholic steatohepatitis, hepatic steatosis, liver injury, senescence-associated secretory phenotype, cellular senescence, macrophage accumulation, dysplastic nodules, Mdr2 knockout mice, sgp130, hepatocyte proliferation
MeSH terms
ATP-Binding Cassette Sub-Family B Member 4, Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Fatty Liver, Female, Immunohistochemistry, Liver Neoplasms, Mice, Transgenic, Biomarkers, Interleukin-6, Cellular Senescence, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Disease Progression, Mice

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