p38γ MAPK is required for inflammation-associated colon tumorigenesis. Oncogene 2016 Feb 25;35(8):1039-48
Date
05/12/2015Pubmed ID
25961922DOI
10.1038/onc.2015.158Scopus ID
2-s2.0-84959509513 (requires institutional sign-in at Scopus site) 32 CitationsAbstract
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.
Author List
Yin N, Qi X, Tsai S, Lu Y, Basir Z, Oshima K, Thomas JP, Myers CR, Stoner G, Chen GAuthors
Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinXiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnti-Inflammatory Agents, Non-Steroidal
Carcinogenesis
Colonic Neoplasms
Cytokines
Enzyme Activation
Humans
Inflammation
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Mitogen-Activated Protein Kinase 12
Neoplasm Transplantation
Pyridones
Signal Transduction
Tumor Cells, Cultured
