MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development.
Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB-dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2(-) (/) (-)AID(+), ALB-MSH2(-) (/) (-), and ALB-AID(+) mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes. The mutation signatures in the tumors developed in these models, especially ALB-MSH2(-) (/) (-)AID(+) mice, closely resembled those of human hepatocellular carcinoma. Our findings demonstrated that inflammation-mediated dysregulation of MSH2 may be a mechanism of genetic alterations during hepatocarcinogenesis. Cancer Res; 76(15); 4383-93. ©2016 AACR.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yuji
Y
Eso
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Atsushi
A
Takai
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tomonori
T
Matsumoto
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tadashi
T
Inuzuka
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takahiro
T
Horie
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Koh
K
Ono
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shinji
S
Uemoto
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.
Kyeryoung
K
Lee
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York.
Winfried
W
Edelmann
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tsutomu
T
Chiba
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. maru@kuhp.kyoto-u.ac.jp.
Hiroyuki
H
Marusawa
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D051379:Mice; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism*
D016207:Cytokines; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein