Abstract 2980: Clinico-pathological correlation of UBE2C alterations in colorectal carcinoma and efficacy of UBE2C inhibition by proteosome inhibitor as a viable therapeutic target

Abstract

Abstract Substantial evidence implicates UBE2C in several human cancers including colorectal carcinoma. We sought to determine the prognostic value of the UBE2C alterations in colorectal cancer (CRC), UBE2C signaling in CRC cell lines and effect of protesome inhibitors in modulating UBE2C expression in vitro and in vivo nude mice xenografts. We examined UBE2C expression by immunohistochemistry and UBE2C gene copy number by FISH in CRC.The oncogenic role of UBE2C in CRC cell lines was explored and potential therapeutic value of Bortezomib in treating CRC by inhibiting UBE2C was also investigated using in vivo and in vitro analysis. UBE2C dysregulation was seen in a large percentage of colorectal carcinomas: 45.9% at the protein level; 30.7 % at the gene copy number and UBE2C alteration in 61.5 % of the CRC. UBE2C dysregulation occurs early in the progression from adenoma to carcinoma sequence and was associated with proliferative marker Ki-67(p=0.0023), accumulation of cyclin A (p=0.0175) and B1 (p=0.0026). UBE2C expression was associated with a poor overall survival (p=0.0267) in all CRC patients and interestingly, in the early stage CRC subgroup, UBE2C expression was an independent (RR 3.67 95% C.I 1.15-14.03) prognostic marker.Thus, the above findings show the potential of targeting UBE2C enzyme in early stage CRC as well as in pre neoplastic adenomatous lesions. In CRC cell lines, UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1, whereas over overexpression of UBE2C promoted cell proliferation. Bortezomib treatment of CRC cells and xenograft downregulated the expression of UBE2C at mRNA as well as protein level, inhibited cell proliferation resulted in accumulation of cyclin A and cyclin B1 and reduced tumor growth. Altogether, our results establish UBE2C as a key molecule in colorectal carcinogenesis and identify a subgroup of CRC patients with high UBE2C alterations showing a poor overall survival. We have also shown for the first time the efficacy of Bortezomib in inhibiting UBE2C expression at the protein as well as the mRNA level and stabilization of cyclin A and B1. These studies may have important implications for future preclinical and clinical studies in CRC aimed at determining the usefulness of a novel strategy for treating CRC with inhibitors of proteasome pathways, either alone or in combination with other agents. Further work is ongoing to check if treatment with the UBE2C siRNA sensitize the cells to Bortezomib treatment or other commonly used colorectal cancer therapies and if Bortezomib-induced tumor regression comparable to conventional chemotherapeutics like oxaliplatin or 5FU treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2980. doi:10.1158/1538-7445.AM2011-2980