title: p38γ MAPK is required for inflammation-associated colon tumorigenesis.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yin
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: X
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Basir
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: K
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Myers
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: G
authors.initials: G
authors.lastname: Stoner
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, MI, USA.|Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, MI, USA.
authors.forename: G
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D063646:Carcinogenesis; D003110:Colonic Neoplasms / Q000201:enzymology*; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011728:Pyridones / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D011728:Pyridones; C093844:pirfenidone; D048291:Mitogen-Activated Protein Kinase 12