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

7 Citations (Scopus)

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

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Liver Neoplasms
Cytokines
Inflammation
Hepatocytes
DNA Mismatch Repair
Genetic Predisposition to Disease
Albumins
Hepatocellular Carcinoma
Carcinogenesis
Down-Regulation
Mutation
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development. / Eso, Yuji; Takai, Atsushi; Matsumoto, Tomonori; Inuzuka, Tadashi; Horie, Takahiro; Ono, Koh; Uemoto, Shinji; Lee, Kye-Ryoung; Edelmann, Winfried; Chiba, Tsutomu; Marusawa, Hiroyuki.

In: Cancer Research, Vol. 76, No. 15, 01.08.2016, p. 4383-4393.

Research output: Contribution to journalArticle

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, vol. 76, no. 15, pp. 4383-4393. https://doi.org/10.1158/0008-5472.CAN-15-2926
Eso, Yuji ; Takai, Atsushi ; Matsumoto, Tomonori ; Inuzuka, Tadashi ; Horie, Takahiro ; Ono, Koh ; Uemoto, Shinji ; Lee, Kye-Ryoung ; Edelmann, Winfried ; Chiba, Tsutomu ; Marusawa, Hiroyuki. / MSH2 dysregulation is triggered by proinflammatory cytokine stimulation and is associated with liver cancer development. In: Cancer Research. 2016 ; Vol. 76, No. 15. pp. 4383-4393.
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