Mutant N-Ras protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression
Menée à l'aide de modèles murins génétiquement modifés, cette étude met en évidence un mécanisme par lequel la protéine exprimée par un gène N-Ras muté favorise, dans un contexte inflammatoire, la tumorigenèse d'un cancer colorectal
N-Ras is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in N-Ras occur in a subset of colorectal cancers, but little in known about how the mutant protein contributes to onset and progression of the disease. Using genetically engineered mice, we find that mutant N-Ras strongly promotes tumorigenesis in the context of inflammation. The pro-tumorigenic nature of mutant N-Ras is related to its anti-apoptotic function, which is mediated by activation of a non-canonical MAPK pathway that signals through Stat3. As a result, inhibition of MEK selectively induces apoptosis in autochthonous colonic tumors expressing mutant N-Ras. The translational significance of this finding is highlighted by our observation that NRAS mutation correlates with a less favorable clinical outcome for colorectal cancer patients. These data demonstrate for the first time the important role that N-Ras plays in colorectal cancer.