Differential expression of small ubiquitin-like modifier family of proteins in patients with colorectal adenocarcinoma.

Abstract

420 Background: The cytotoxic effects of radiation and chemotherapy are mediated in part by DNA damage. The small ubiquitin-like modifier (SUMO) family of proteins regulates DNA repair pathways by activating factors involved in homologous recombination (HR) or non- homologous end joining (NHEJ). Our objective was to determine the potential role of SUMO proteins in patients with colorectal cancer. Methods: We first assessed two established colorectal cancer cell lines (HCT116 and HT29) and two normal colonic mucosa cell populations utilizing ultra high-throughput expression analysis (Solexa) to examine differential expression of genes involved in SUMOylation (SAE1, SAE2, PIAS-1, and DNAPKcs). To verify the clinical relevance of SUMOylation in colorectal cancer, we obtained archived specimens from patients with colorectal cancer (n=51) and examined the expression of these proteins in both benign and malignant tissue by immunohistochemistry (IHC). Results: Ultra high-throughput expression analysis of cancer and normal cells revealed a 10 to 15-fold upregulation of SAE2 (heterodimer of the E1 activation enzyme in SUMOylation), a 10 to 11-fold upregulation of DNAPKcs (catalytic subunit in NHEJ repair pathway), and a 6-fold upregulation of SAE1 in cancer cells. In contrast, PIAS-1 showed similar expression levels between cancer and normal colonic cells. By IHC, SAE1 and SAE2 were highly expressed in 65% and 53% of tumor specimens, respectively; but only in 7% and 0% of normal tissues, respectively. DNAPKcs was also highly expressed in tumor tissues (63%) with corresponding low expression (0%) in normal tissues. Corroborating the cell line results, PIAS-1 was infrequently expressed in both tumor (10%) and normal tissues (0%). Conclusions: We are the first to demonstrate the differential expression of SUMO proteins in colorectal cancer cell lines and in clinical specimens. SUMO proteins have a role in DNA repair and their expression in colorectal cancer may modify tumor response to chemoradiotherapy. No significant financial relationships to disclose.