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

被引：435

作者：

Nakagawa, Hayato ^{[1
,5
]}

Umemura, Atsushi ^{[1
]}

Taniguchi, Koji ^{[1
]}

Font-Burgada, Joan ^{[1
]}

Dhar, Debanjan ^{[1
]}

Ogata, Hisanobu ^{[1
,6
]}

Zhong, Zhenyu ^{[1
]}

Valasek, Mark A. ^{[2
]}

Seki, Ekihiro ^{[3
]}

Hidalgo, Juan ^{[4
]}

Koike, Kazuhiko ^{[5
]}

Kaufman, Randal J. ^{[7
]}

Karin, Michael ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, San Diego, CA 92093 USA

[2] Univ Calif San Diego, Sch Med, Dept Pathol, San Diego, CA 92093 USA

[3] Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA 92093 USA

[4] Univ Autonoma Barcelona, Inst Neurosci, Dept Cell Biol Physiol & Immunol, E-08193 Barcelona, Spain

[5] Univ Tokyo, Dept Gastroenterol, Bunkyo Ku, Tokyo 1138655, Japan

[6] Kyushu Univ, Grad Sch Med Sci, Dept Med & Clin Sci, Fukuoka 8128582, Japan

[7] Sanford Burnham Med Res Inst, Program Degenerat Dis, La Jolla, CA 92037 USA

来源：

CANCER CELL | 2014年 / 26卷 / 03期

基金：

日本学术振兴会;

关键词：

ENDOPLASMIC-RETICULUM STRESS; FATTY LIVER-DISEASE; HEPATOCELLULAR-CARCINOMA; HEPATIC STEATOSIS; ACTIVATION; OBESITY; STEATOHEPATITIS; IDENTIFICATION; INFLAMMATION; INSULIN;

D O I：

10.1016/j.ccr.2014.07.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：331 / 343

页数：13

共 33 条

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