Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression
2012; American Association for Cancer Research; Volume: 3; Issue: 3 Linguagem: Inglês
10.1158/2159-8290.cd-12-0198
ISSN2159-8290
AutoresYufang Wang, Sérgia Velho, Efsevia Vakiani, Shouyong Peng, Adam J. Bass, Gerald C. Chu, Jessica J. Gierut, James M. Bugni, Channing J. Der, Mark R. Philips, David B. Solit, Kevin M. Haigis,
Tópico(s)FOXO transcription factor regulation
ResumoAbstract 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. Significance: Little is known about N-RAS function in normal biology or in cancer. Our study links the antiapoptotic function of mutant N-RAS to its ability to promote colorectal cancer in an inflammatory context. In addition, our study pinpoints a therapeutic strategy for this distinct colorectal cancer subtype. Cancer Discov; 3(3); 294–307. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 239
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