Expression of selenium-binding protein 1 characterizes intestinal cell maturation and predicts survival for patients with colorectal cancer

To identify candidate genes involved in the development of colorectal cancer, we used cDNA micro- arrays to analyze gene expression differences between human colorectal tumors and paired adjacent normal mucosa. We identified l3.5-fold significant downregulation of selenium-binding protein 1 (SBP1) in colorectal tumors compared to normal mucosa (p = 0.003). Importantly, stage III colorectal cancer patients with low tumor-SBP1 expression had significantly shorter disease-free and overall survival as compared with those patients with high tumor-SBP1 expression (p = 0.04 and 0.03, respectively). We further characterized the role of SBP1 in colorectal cancer in vivo and in vitro .I n normal tissue, SBP1 was maximally expressed in terminally differentiated epithelial cells on the lumi- nal surface of crypts in the large intestine. Consistent with this in vivo localization, SBP1 was upregu- lated during in vitro colonic cell differentiation along the absorptive (Caco-2) and secretory (HT29 Clones 16E and 19A) cell lineages. Downregulation (approximately 50%) of SBP1 expression by small interfering RNA in colonic cancer cells was associated with reduced expression of another epi- thelial differentiation marker, carcinoembryonic antigen (CEA), although PCNA and p21 WAF1/cip1 expression were not altered. These data demonstrate that higher expression of SBP1 is associated with differentiation of the normal colonic epithelia and may be a positive prognostic factor for sur- vival in stage III colorectal carcinoma.