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 journalArticlepeer-review

207 Scopus citations

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 (US)
Pages (from-to)331-343
Number of pages13
JournalCancer Cell
Volume26
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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