Mutant N-RAS Protects Colorectal Cancer Cells from Stress-Induced Apoptosis and Contributes to Cancer Development and Progression

Cancer Discovery - Tập 3 Số 3 - Trang 294-307 - 2013
Yufang Wang1,2,3,4,5,6,7, Sérgia Velho1,2,3,4,5,6,7, Efsevia Vakiani1,2,3,4,5,6,7, Shouyong Peng1,2,3,4,5,6,7, Adam J. Bass1,2,3,4,6,7, Gerald C. Chu1,2,4,6,7, Jessica J. Gierut1,2,3,4,5,6,7, James M. Bugni1,2,3,4,5,6,7, Channing J. Der1,2,3,4,5,6,7, Mark R. Philips1,2,3,4,5,6,7, David B. Solit1,2,3,4,5,6,7, Kevin M. Haigis1,2,3,4,5,6,7
1Authors' Affiliations: 1Molecular Pathology Unit, Center for Cancer Research and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Charlestown; 2Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute; Departments of 3Medicine and 4Pathology, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts; Departments of 5Pathology and 6Medicine, Memorial Sloan-Kettering Cancer Center; 7New York University Cancer Institute, New York University School of Medicine, New York, New York; 8Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; 9Lineberger Comprehensive Cancer Center and Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina
2Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute
3Departments of Medicine and Pathology, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts
4Departments of Pathology and Medicine, Memorial Sloan-Kettering Cancer Center
5Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
6Lineberger Comprehensive Cancer Center and Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina
7New York University Cancer Institute, New York University School of Medicine, New York, New York

Tóm tắt

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.

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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Cancer Discovery

Tập 3 Số 3

294-307

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