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Cancer Discov. 2013 Mar;3(3):294-307. doi: 10.1158/2159-8290.CD-12-0198. Epub 2012 Dec 28.

Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression.

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Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129 , USA.


N-RAS is one member of a family of oncoproteins that are commonly mutated in cancer. Activating mutations in NRAS occur in a subset of colorectal cancers, but little is known about how the mutant protein contributes to the 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 protumorigenic nature of mutant N-RAS is related to its antiapoptotic function, which is mediated by activation of a noncanonical mitogen-activated protein kinase pathway that signals through STAT3. As a result, inhibition of MAP-ERK kinase 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 patients with colorectal cancer. These data show for the first time the important role that N-RAS plays in colorectal cancer.

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