P38γ MAPK is required for inflammation-associated colon tumorigenesis

N. Yin, X. Qi, S. Tsai, Y. Lu, Z. Basir, K. Oshima, J. P. Thomas, C. R. Myers, G. Stoner, G. Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic inflammation has long been considered to causatively link to colon cancer development. However, signal transduction pathways involved remain largely unidentified. Here, we report that p38γ mitogen-activated protein kinase mediates inflammatory signaling to promote colon tumorigenesis. Inflammation activates p38γ in mouse colon tissues and intestinal epithelial cell-specific p38γ knockout (KO) attenuates colitis and inhibits pro-inflammatory cytokine expression. Significantly, p38γ KO inhibits tumorigenesis in a colitis-associated mouse model. The specific p38γ pharmacological inhibitor pirfenidone also suppresses pro-inflammatory cytokine expression and colon tumorigenesis. The tumor-promoting activity of epithelial p38γ was further demonstrated by xenograft studies. In addition, p38γ is required for β-catenin/Wnt activities and p38γ stimulates Wnt transcription by phosphorylating β-catenin at Ser605. These results show that p38γ activation links inflammation and colon tumorigenesis. Targeting p38γ may be a novel strategy for colon cancer prevention and treatment.

Original languageEnglish (US)
Pages (from-to)1039-1048
Number of pages10
JournalOncogene
Volume35
Issue number8
DOIs
StatePublished - Feb 25 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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