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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)331-343
Number of pages13
JournalCancer Cell
Volume26
Issue number3
DOIs
Publication statusPublished - Jan 1 2014

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Overnutrition
Endoplasmic Reticulum Stress
Hepatocellular Carcinoma
Hepatocytes
Liver
Lipogenesis
Plasminogen Activators
High Fat Diet
Hepatitis
Insulin Resistance
Carcinogenesis
Obesity
Macrophages
Insulin
Non-alcoholic Fatty Liver Disease

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Nakagawa, H., Umemura, A., Taniguchi, K., Font-Burgada, J., Dhar, D., Ogata, H., ... Karin, M. (2014). ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development. Cancer Cell, 26(3), 331-343. https://doi.org/10.1016/j.ccr.2014.07.001

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

In: Cancer Cell, Vol. 26, No. 3, 01.01.2014, p. 331-343.

Research output: Contribution to journalArticle

Nakagawa, H, Umemura, A, Taniguchi, K, Font-Burgada, J, Dhar, D, Ogata, H, Zhong, Z, Valasek, MA, Seki, E, Hidalgo, J, Koike, K, Kaufman, RJ & Karin, M 2014, 'ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development', Cancer Cell, vol. 26, no. 3, pp. 331-343. https://doi.org/10.1016/j.ccr.2014.07.001
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. / ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development. In: Cancer Cell. 2014 ; Vol. 26, No. 3. pp. 331-343.
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