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

doi:10.1016/j.ccr.2014.07.001

ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development

Cancer Cell. 2014 Sep 8;26(3):331-343. doi: 10.1016/j.ccr.2014.07.001. Epub 2014 Aug 14.

Authors

Affiliations

¹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
² Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
³ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
⁴ Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
⁵ Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
⁶ Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.
⁷ Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
⁸ Program in Degenerative Diseases, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinoma, Hepatocellular / etiology
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology
Cells, Cultured
Diet, High-Fat / adverse effects
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress*
Fatty Liver / etiology
Fatty Liver / metabolism
Heat-Shock Proteins / metabolism
Lipogenesis
Liver Neoplasms, Experimental / etiology
Liver Neoplasms, Experimental / metabolism*
Liver Neoplasms, Experimental / pathology
Male
Mice
Mice, Transgenic
Overnutrition / complications*
Receptors, Tumor Necrosis Factor, Type I / metabolism
Signal Transduction
Tumor Burden
Tumor Necrosis Factor-alpha / physiology*
Urokinase-Type Plasminogen Activator / genetics
Urokinase-Type Plasminogen Activator / metabolism

Substances

Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins
Receptors, Tumor Necrosis Factor, Type I
Tnfrsf1a protein, mouse
Tumor Necrosis Factor-alpha
Urokinase-Type Plasminogen Activator

Abstract

Publication types

MeSH terms

Substances

Grants and funding