Abstract 2147: Co-expression of cyclooxygenase-2 and FoxM1 is an independent prognostic marker for poor outcome in Stage II and III colorectal carcinoma
Authors: Jehan Zeenath , Ahmed Maqbool , Bavi Prashant , Hussain Azhar R. , Al-Sanea Nasser , AbdulJabbar Alaa , Ashari Luai , Al-Homoud Samar , Al-Dayel Fouad , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
Cox-2 and FoxM1 are extensively studied and both have been implicated in colorectal carcinogenesis. Therefore, the FoxM1 may represent a novel therapeutic target, and thus the development of agents that will target FoxM1 is likely to have significant therapeutic impact on human cancer. We studied COX2 and FoxM1 expression in a tissue microarray cohort of more than 400 colorectal carcinomas, Cox-2 and FoxM1 signaling in in vitro in CRC cell lines. Incidence of Cox-2 and FoxM1 expression in all CRC cases was 66.2 %(245/370) & 53.8%(211/392) respectively. Cox-2 expression in all CRC's(Stage I – IV) was associated with an aggressive phenotype characterized by poorly differentiated tumors, lymph node metastasis, histology type of mucinous carcinoma and proliferative marker Ki-67. Interestingly Cox-2 expression was associated with expression of FoxM1 (p=0.0226). Considering the fact that both Cox-2 and Foxm1 have been implicated in colorectal carcinogenesis and the potential therapeutic utility of both these markers we grouped our cases based on expression on Cox-2 and FoxM1 in Stage II and Stage III CRC's only. Co-expression of both Cox-2 and FoxM1 was seen in 42.4% (104/245) of CRC's and was again associated with an aggressive phenotype characterized by by poorly differentiated tumors, lymph node metastasis, histology type of mucinous carcinoma, proliferative marker Ki-67, overexpression of MMP9(p=0.0061) and KRAS mutations(p=0.0011). Kaplan Meier survival analysis in the Stage II-III subgroup showed that both over-expression of Cox-2(p=0385) and co-expression of Cox-2 and FoxM1 (p=0.0228) was associated with poor overall survival. In the multivariate analysis using Cox Proportional Hazard model for multiple factors like age, gender, tumor differentiation and co-expression of Cox-2 and FoxM1 the relative risk was 1.77 for co- expression of Cox-2 and FoxM1 (95% CI 1.05-3.03); p = 0.0317) and 1.58 for tumor differentiation. (95% CI 0.85-2.80; p =0.1417). Thus, co-expression of Cox-2 and FoxM1 was an independent prognostic marker for poor overall survival in the Stage II-III subset of colorectal carcinoma. Our in vitro studies showed that co-inhibition of FoxM1 and Cox-2 with pharmacological inhibitors resulted a synergistic effect on apoptosis in CRC cell lines. Cox-2 siRNA and NS398 treatment had no effect on the expression of FoxM1. Similarly treatment of Xenografts tumors in nude mice had no effect on FoxM1 expression suggesting that FoxM1 is functional upstream of Cox-2. These findings demonstrates that Co-expression of Cox-2 and FoxM1 play critical role in the pathogenesis of CRC and a novel therapeutic target for the treatment of stage II and III CRC.
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 2147. doi:10.1158/1538-7445.AM2011-2147