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.

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 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

  • Heat-Shock Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Urokinase-Type Plasminogen Activator
  • molecular chaperone GRP78