title: Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression.
abstract: 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.
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129 , USA.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Wang
authors.forename: Sérgia
authors.initials: S
authors.lastname: Velho
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Shouyong
authors.initials: S
authors.lastname: Peng
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Jessica
authors.initials: J
authors.lastname: Gierut
authors.forename: James M
authors.initials: JM
authors.lastname: Bugni
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
authors.forename: Mark
authors.initials: M
authors.lastname: Philips
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D018631:ras Proteins