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p38γ MAPK is required for inflammation-associated colon tumorigenesis

Oncogene volume 35, pages 1039–1048 (2016)Cite this article

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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.

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Acknowledgements

We thank Boehringer Ingelheim Pharmaceuticals Inc. and Dr Zhen Yan (University of Virginia) for providing the floxed p38γ mice. We also thank former lab members Drs PS Suresh for maintaining mice and conducting some preliminary experiments, and S Hou for generating the p38γ-depleted HCT116 cell lines. In addition, we express our gratitude to Drs D Wang (Blood Institute of Wisconsin), A Chan, R Li and J Tichelaar (Medical College of Wisconsin) for useful discussions. We also thank Drs J Han (The Scripps Research Institute), A Cuenda (National Center for Biotechnology-CSIC), NK Tonks (Cold Spring Harbor) and H Howe (South Carolina University) for providing various reagents. This work was in part supported by the grants from the Department of Veterans Affairs Merit Review (I01BX002883), the Cancer Center of Medical College of Wisconsin (the State of Wisconsin Tax Check-Off Program), and Clinical & Translational Science Institute (CTSI) of Southeast Wisconsin (to GC).

Author Contributions

NY performed experiments, analyzed results and generated figures. XQ, GC, ZB and KO also participated in performing experiments. NY, XQ and GC designed experiments and interpreted results; GS, ST, JPT and CRM contributed ideas; and LY participated in data analysis. NY, CRM and GC wrote the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, MI, USA,

    N Yin, X Qi, C R Myers & G Chen

  2. Department of Surgery, Medical College of Wisconsin, Milwaukee, MI, USA,

    S Tsai

  3. Department of Physiology, Medical College of Wisconsin, Milwaukee, MI, USA,

    Y Lu

  4. Department of Pathology, Medical College of Wisconsin, Milwaukee, MI, USA,

    Z Basir & K Oshima

  5. Department of Medicine, Medical College of Wisconsin, Milwaukee, MI, USA,

    J P Thomas & G Stoner

  6. Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, MI, USA

    G Chen

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  1. N Yin
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Correspondence to G Chen.

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Yin, N., Qi, X., Tsai, S. et al. p38γ MAPK is required for inflammation-associated colon tumorigenesis. Oncogene 35, 1039–1048 (2016). https://doi.org/10.1038/onc.2015.158

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