ABSTRACT
CDX2 is a Drosophila caudal-related homeobox transcription factor that is important for the establishment and maintenance of intestinal epithelial cells. We have reported that CDX2 promotes tumorigenicity in a subset of human colorectal cancer cell lines. Here, we present evidence that CDX2 negatively regulates the well-documented growth inhibitor insulin-like growth factor binding protein-3 (IGFBP-3). Specifically, CDX2 binds to the IGFBP-3 gene promoter and can repress IGFBP-3 transcription, protein expression and secretion. Furthermore, inhibition of IGFBP-3 partially rescues the decreased anchorage-independent growth phenotype observed in CDX2 knockout cells. These data demonstrate for the first time that (1) CDX2 can function as a transcriptional repressor, and (2) one mechanism by which CDX2 promotes anchorage-independent growth is by transcriptional repression of IGFBP-3.
Subject(s)
Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/metabolism , Insulin-Like Growth Factor Binding Proteins/genetics , Repressor Proteins/metabolism , CDX2 Transcription Factor , Cell Line, Tumor , Down-Regulation , Homeodomain Proteins/genetics , Humans , Insulin-Like Growth Factor Binding Protein 3 , Promoter Regions, Genetic , Repressor Proteins/genetics , Transcription, Genetic , Up-RegulationABSTRACT
Deletions of chromosome sequences mapping to the short arm of chromosome 8 have been observed frequently in a variety of human cancers. A small number of studies have suggested that the terminal portion of the short arm of chromosome 8, 8pter-p23, may be deleted independently of other portions of 8p in human tumors, and that deletion of the 8pter-p23 region may be correlated with poor prognosis. The aim of the present study was to physically define the minimal region of 8pter-p23 deletion and to define the frequency and prognostic significance of 8pter-p23 loss in human prostate tumors. DNA was purified from normal and tumor tissues of 45 radical prostatectomy specimens and amplified for 15 highly polymorphic microsatellite sequences, 13 spanning 8pter-p23 and 2 proximal 8p markers. Allelic loss of 8p sequences was observed in 28 of 45 (62%) tumors examined. Of these, approximately half (12 of 28; 43%) demonstrated independent loss of the 8pter-p23 region, with several tumors defining a 5-cM minimal region of deletion spanning D8S264-D8S1824-D8S1781-D8S262-D8S1798. When serum prostate-specific antigen was used as a surrogate end point marker for survival, 8pter-p23 loss was significantly associated with reduced disease-free progression (log-rank P = 0.0426). Moreover, loss of the 8pter-p23 region was significantly associated with poor survival for American Caucasian (log-rank P = 0.0024) but not African-American (log-rank P = 0.5832) prostate cancer patients. These studies suggest that independent deletion of 8pter-p23 is differentially associated with disease recurrence and poor outcome in American Caucasian but not African-American prostate cancer patients.
