CDX2 is an amplified lineage-survival oncogene in colorectal cancer.
Proc Natl Acad Sci U S A, 2012/11/13;109(46):E3196-205.
Salari K[1], Spulak ME, Cuff J, Forster AD, Giacomini CP, Huang S, Ko ME, Lin AY, van de Rijn M, Pollack JR
Affiliations
PMID: 23112155DOI: 10.1073/pnas.1206004109
Impact factor: 12.779
Abstract
The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.
MeSH terms
Animals; CDX2 Transcription Factor; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 13; Colorectal Neoplasms; Disease Models, Animal; Gene Amplification; Homeodomain Proteins; Humans; Mice; NIH 3T3 Cells; Transcription Factors; Tumor Suppressor Proteins; Wnt Signaling Pathway
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