TY - JOUR
T1 - MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development
AU - Eso, Yuji
AU - Takai, Atsushi
AU - Matsumoto, Tomonori
AU - Inuzuka, Tadashi
AU - Horie, Takahiro
AU - Ono, Koh
AU - Uemoto, Shinji
AU - Lee, Kyeryoung
AU - Edelmann, Winfried
AU - Chiba, Tsutomu
AU - Marusawa, Hiroyuki
N1 - Funding Information:
The authors thank Dr. T. Honjo for his generous gift of AID cTg mice. The authors also thank Drs. K. Takahashi and Y. Ueda for helpful suggestions and Drs. S. K. Kim, T. Shimizu, and Y. Matsumoto for help with the analysis. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research, KAKENHI (26293172), and the Research Program on Hepatitis from Japan Agency for Medical Research and Development, AMED, Japan, and NIH grants (CA76329 and CA13330). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-15-2926
DO - 10.1158/0008-5472.CAN-15-2926
M3 - Article
C2 - 27261510
AN - SCOPUS:84982685065
SN - 0008-5472
VL - 76
SP - 4383
EP - 4393
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -
