Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis

Anat Shriki; Tali Lanton; Amir Sonnenblick; Orr Levkovitch-Siany; Dana Eidelshtein; Rinat Abramovitch; Nofar Rosenberg; Orit Pappo; Sharona Elgavish; Yuval Nevo; Rifaat Safadi; Amnon Peled; Stefan Rose-John; Eithan Galun; Jonathan H. Axelrod

doi:10.1158/0008-5472.CAN-21-0321

Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis

Anat Shriki, Tali Lanton, Amir Sonnenblick, Orr Levkovitch-Siany, Dana Eidelshtein, Rinat Abramovitch, Nofar Rosenberg, Orit Pappo, Sharona Elgavish, Yuval Nevo, Rifaat Safadi, Amnon Peled, Stefan Rose-John, Eithan Galun, Jonathan H. Axelrod

Tel Aviv University, The Hebrew University of Jerusalem

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Pages (from-to)	4766-4777
Number of pages	12
Journal	Cancer Research
Volume	81
Issue number	18
DOIs	https://doi.org/10.1158/0008-5472.CAN-21-0321
State	Published - 15 Sep 2021

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-21-0321

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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. (2021). Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis. Cancer Research, 81(18), 4766-4777. https://doi.org/10.1158/0008-5472.CAN-21-0321

@article{452d1cbfca9748ec8c959bf497c90045,

title = "Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis",

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 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.",

author = "Anat Shriki and Tali Lanton and Amir Sonnenblick and Orr Levkovitch-Siany and Dana Eidelshtein and Rinat Abramovitch and Nofar Rosenberg and Orit Pappo and Sharona Elgavish and Yuval Nevo and Rifaat Safadi and Amnon Peled and Stefan Rose-John and Eithan Galun and Axelrod, {Jonathan H.}",

note = "Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = sep,

day = "15",

doi = "10.1158/0008-5472.CAN-21-0321",

language = "الإنجليزيّة",

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publisher = "American Association for Cancer Research Inc.",

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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, JH 2021, 'Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis', Cancer Research, vol. 81, no. 18, pp. 4766-4777. https://doi.org/10.1158/0008-5472.CAN-21-0321

TY - JOUR

T1 - Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis

AU - Shriki, Anat

AU - Lanton, Tali

AU - Sonnenblick, Amir

AU - Levkovitch-Siany, Orr

AU - Eidelshtein, Dana

AU - Abramovitch, Rinat

AU - Rosenberg, Nofar

AU - Pappo, Orit

AU - Elgavish, Sharona

AU - Nevo, Yuval

AU - Safadi, Rifaat

AU - Peled, Amnon

AU - Rose-John, Stefan

AU - Galun, Eithan

AU - Axelrod, Jonathan H.

PY - 2021/9/15

Y1 - 2021/9/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85114989627&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-21-0321

DO - 10.1158/0008-5472.CAN-21-0321

M3 - مقالة

C2 - 34117031

SN - 0008-5472

VL - 81

SP - 4766

EP - 4777

JO - Cancer Research

JF - Cancer Research

IS - 18

ER -

Multiple roles of il6 in hepatic injury, steatosis, and senescence aggregate to suppress tumorigenesis

Abstract

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