Cited by 526Endoplasmic Reticulum Stress and DiseaseCancer, Lipids, and MetabolismLiver Disease Diagnosis and Treatment

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ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development

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Nakagawa, Hayato, Umemura, Atsushi, Taniguchi, Koji, Font-Burgada, Joan, Dhar, Debanjan, Ogata, Hisanobu, Zhong, Zhenyu, Valasek, Mark A., Seki, Ekihiro, Hidalgo, Juan, Koike, Kazuhiko, Kaufman, Randal J., Karin, Michael·2014·Cancer Cell

DOI 10.1016/j.ccr.2014.07.001PMC PMC4165611

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Abstract

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.

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Authors: Nakagawa, H., Umemura, A., Taniguchi, K., Font-Burgada, J., Dhar, D., Ogata, H., Zhong, Z., Valasek, M. A., Seki, E., Hidalgo, J., Koike, K., Kaufman, R. J., & Karin, M.
Affiliations: University of California San Diego (US)
Kyushu University (JP)
Universitat Autònoma de Barcelona (ES)
The University of Tokyo (JP)
Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author: Karin, Michael
ORCID: Nakagawa, Hayato
Umemura, Atsushi
Taniguchi, Koji
Font-Burgada, Joan
Dhar, Debanjan
Zhong, Zhenyu
Valasek, Mark A.
Seki, Ekihiro
Hidalgo, Juan
Koike, Kazuhiko
Kaufman, Randal J.
Karin, Michael
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2014-09
Volume: 26
Issue: 3
Pages: 331-343
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2014.07.001
PMC: PMC4165611
OpenAlex: W2085390667
Cited by: 525
References: 38
Citations by year: 2026: 22 · 2025: 38 · 2024: 43 · 2023: 58 · 2022: 57 · 2021: 57 · 2020: 56 · 2019: 40 · 2018: 42 · 2017: 34 · 2016: 39 · 2015: 28 · 2014: 11
FWCI: 18.59
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 388 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Japan Society for the Promotion of Science (24390183)
National Heart, Lung, and Blood Institute (R01HL052173, HL052173-16)
National Cancer Institute (R01CA118165, CA155120-02, R01CA155120, P30CA023100, CA118165-06)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088227, DK042394-18, DK088227-06)
National Institute of Environmental Health Sciences (P42ES010337)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Keywords: endoplasmic reticulum stress, overnutrition, hepatocellular carcinoma, nonalcoholic steatohepatitis, TNF-α, plasminogen activator, high-fat diet, insulin resistance, hepatic steatosis, inflammatory macrophages, lipogenesis
MeSH terms: Endoplasmic Reticulum Chaperone BiP, Animals, Cells, Cultured, Fatty Liver, Heat-Shock Proteins, Carcinoma, Hepatocellular, Liver Neoplasms, Experimental, Male, Mice, Transgenic, Tumor Necrosis Factor-alpha, Urokinase-Type Plasminogen Activator, Signal Transduction, Overnutrition, Tumor Burden, Receptors, Tumor Necrosis Factor, Type I, Lipogenesis, Mice, Diet, High-Fat, Endoplasmic Reticulum Stress

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