Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apc min/+ mice, but the mechanisms by which Apc enhances tumor growth are unknown. Here we show that microflora-MyD88-ERK signaling in intestinal epithelial cells (IECs) promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein.
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Activation of ERK (extracellular signal–related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apc min/+ /Myd88 −/− mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apc min/+ mice. MyD88 (myeloid differentiation primary response gene 88)-independent activation of ERK by epidermal growth factor (EGF) increased p-ERK and c-Myc and restored the multiple intestinal neoplasia (Min) phenotype in Apc min/+ /Myd88 −/− mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apc min/+ /Myd88 −/− and Apc min/+ mice and increased their survival.
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