TY - JOUR
T1 - ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development
AU - Nakagawa, Hayato
AU - Umemura, Atsushi
AU - Taniguchi, Koji
AU - Font-Burgada, Joan
AU - Dhar, Debanjan
AU - Ogata, Hisanobu
AU - Zhong, Zhenyu
AU - Valasek, Mark A.
AU - Seki, Ekihiro
AU - Hidalgo, Juan
AU - Koike, Kazuhiko
AU - Kaufman, Randal J.
AU - Karin, Michael
N1 - Funding Information:
We thank Dr. E.P. Sandgren for MUP-uPA, Dr. I. Tabas for Chop F/F mice, and Dr. M.R. Mackey, Dr. G.A. Perkins, and Dr. M.H. Ellisman for help with the EM analysis. Research was supported by the Daiichi Sankyo Foundation of Life Science and Grant-in-Aid for Scientific Research (#25893042), and the Astellas Foundation for Research on Metabolic Disorders (H.N.); a Global Grant Scholarship from The Rotary Foundation (A.U.); a postdoctoral fellowship for Research Abroad, Research Fellowship for Young Scientists from the Japan Society for the Promotion of Science, and the Uehara Memorial Foundation Fellowship (K.T.); California Institute for Regenerative Medicine Stem Cell Training Grant II (TG2-01154; J.F.B.); the American Liver Foundation and a Young Investigator Award from the National Childhood Cancer Foundation “CureSearch” (D.D.); the Kanzawa Medical Research Foundation (H.O.); Cancer Research Institute Irvington Postdoctoral Fellowship (Z.Z.); grants from the NIH (CA155120-02 and CA118165-06; M.K.) and (DK042394-18, DK088227-06, and HL052173-16; R.J.K.), and Superfund Basic Research Program (P42ES010337; E.S. and M.K.). M.K. holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases and is an American Cancer Society Research Professor.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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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U2 - 10.1016/j.ccr.2014.07.001
DO - 10.1016/j.ccr.2014.07.001
M3 - Article
C2 - 25132496
AN - SCOPUS:84908665169
SN - 1535-6108
VL - 26
SP - 331
EP - 343
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
