ERK activation drives intestinal tumorigenesis in Apcmin/+ mice

TLR signaling is essential for intestinal tumorigenesis in Apcmin/+ mice, but the mechanisms by which this protein enhances tumor growth are unknown. Here we show that the Microflora-MyD88-ERK signaling in intestinal epithelial cells (IEC) promotes tumorigenesis by increasing the stability of the c-myc oncoprotein. Activation of ERK phosphorylates c-myc that prevents its ubiquitination and its subsequent proteasomal degradation. Accordingly, Apcmin/+/Myd88-/- mice display reduced levels of pERK and c-myc proteins in IEC, and a low incidence of IEC tumors. A MyD88-independent activation of ERK by EGF increases pERK and c-myc levels and restores the Min phenotype in Apcmin/+/Myd88-/- mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apcmin/+/Myd88-/- and in Apcmin/+ mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, where the microflora-induced TLR activation regulates the expression of an oncogene that leads to IEC tumor growth in a susceptible host