American Association for Cancer Research
00085472can152926-sup-157072_2_supp_3469652_h6c92h.png (65.36 kB)

Supplementary Figure S3 from MSH2 Dysregulation Is Triggered by Proinflammatory Cytokine Stimulation and Is Associated with Liver Cancer Development

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posted on 2023-03-30, 23:48 authored by Yuji Eso, Atsushi Takai, Tomonori Matsumoto, Tadashi Inuzuka, Takahiro Horie, Koh Ono, Shinji Uemoto, Kyeryoung Lee, Winfried Edelmann, Tsutomu Chiba, Hiroyuki Marusawa

MSH2 is downregulated and miR-21 is upregulated in HCV-related human hepatitis tissues.



Japan Agency for Medical Research and 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.