Abstract
Abstract Our goal is to determine how transcriptional regulatory mechanisms that control crypt cell maturation in normal colonic epithelium, when dysregulated, lead to maturation arrest, tumor stem cell (SC) overpopulation and colorectal cancer (CRC) development. Accordingly, we studied changes in maturation during colon cancer development caused by APC mutations. Quantitative mapping of crypt cell subpopulations was done on colon tissues from FAP patients using markers for stem cells (SC), proliferating cells, cell-cycle arrest, and apoptosis. In normal human colon, mapping defined the sequential transitions in colonic crypts that enterocyte subpopulations undergo during their maturation from stem-to-proliferating-to-differentiated-to-apoptotic cells, illustrating the point that maturation is a process involving both proliferation and differentiation. In normal-appearing (heterozygous-mutant) and adenomatous (homozygous-mutant) FAP crypts, SC and proliferating cell subpopulations increasingly expanded towards the crypt top, while differentiated/apoptotic subpopulations in the upper crypt contracted, indicating that crypt cell maturation becomes progressively delayed. These data indicate that there are coordinated mechanisms that regulate maturation of crypt cells in normal crypts which become dysregulated in premalignant crypts. To investigate possible transcriptional regulation of a network of genes underlying maturation, we used bioinformatic tools to identify (i) genes that are co-expressed in the proliferating cell population and (ii) transcriptional regulatory elements (TREs) statistically enriched in the promoter regions among those genes. Computational analysis revealed (i) a specific cassette of sixty-six genes that are co-expressed with the markers used for mapping the proliferating cell population in the lower colonic crypt and (ii) eleven TREs that are significantly enriched in the promoter regions among genes in this gene set. Quantitative PCR and immunohistochemistry was then used to validate that the transcription factors (TFs), which correspond to the common TREs, are differentially expressed along the normal crypt axis and in normal colonic epithelium versus malignant colon tissues. Our results indicate that dysregulation of a transcriptional regulatory network contributes to delayed crypt cell maturation, SC overpopulation, and initiation and promotion of CRC. Accordingly, restoring maturation by targeting transcriptional pathways that control expression of multiple genes involved in crypt cell maturation may be a therapeutically effective approach to CRC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4924. doi:1538-7445.AM2012-4924
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