ERK activation drives intestinal tumorigenesis in Apcmin/+ mice

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Abstract
This study dissects the contribution of TLR signaling to intestinal tumorigenesis. MyD88 signaling, known to be required for tumorigenesis in Apcmin/+ mice, is shown to be triggered by ligands from the microflora. MyD88-mediated activation of the MEK-ERK cascade stabilizes c-Myc by preventing its ubiquitin-mediated degradation. The findings link oncogenic c-Myc function to immune signaling and uncover MEK inhibition as a new therapeutic strategy to treat intestinal tumors. Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apcmin/+ 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. Activation of ERK (extracellular signal–related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apcmin/+/Myd88−/− mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apcmin/+ 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 Apcmin/+/Myd88−/− mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apcmin/+/Myd88−/− and Apcmin/+ mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, in which microflora-induced TLR activation regulates oncogene expression and related IEC tumor growth in a susceptible host.