MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development

Yuji Eso, Atsushi Takai, Tomonori Matsumoto, Tadashi Inuzuka, Takahiro Horie, Koh Ono, Shinji Uemoto, Kye-Ryoung Lee, Winfried Edelmann, Tsutomu Chiba, Hiroyuki Marusawa

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4383-4393
Number of pages11
JournalCancer Research
Volume76
Issue number15
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

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  • Cite this

    Eso, Y., Takai, A., Matsumoto, T., Inuzuka, T., Horie, T., Ono, K., Uemoto, S., Lee, K-R., Edelmann, W., Chiba, T., & Marusawa, H. (2016). MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development. Cancer Research, 76(15), 4383-4393. https://doi.org/10.1158/0008-5472.CAN-15-2926