Abstract B35: Aberrant expression of ABCC3 in rectal cancer predicts poor prognosis and pathological response to neoadjuvant chemoradiotherapy via activating the caspase-3 dependent apoptotic pathway

Objective: To clarify the role of ATP binding cassette subfamily C member 3 (ABCC3) on prognosis and pathological response to neoadjuvant chemoradiotherapy in rectal cancer, and further explore the potential molecular mechanism. Design: Retrospective analysis of clinicopathologic factors and detection of ABCC3 expression in pretreatment biopsy specimens from 144 cases of stage II–III rectal cancer who received neoadjuvant chemoradiotherapy and radical surgery. Pathological response according to tumor regression grade and long-term survival curve were further determined. ABCC3 expression was down-regulated using short interfering RNA in colorectal carcinoma cells HT-29 and SW-480. Cell proliferation and apoptosis in response to 5-fluorouracil or irradiation were examined using colony formation assay, single-hit multi-target model, flow cytometry and Hoechst 33342 staining, respectively. Tumor growth following fractional irradiation was measured in xenograft mouse model. Change of intracellular reactive oxygen species contents and activation of cleaved caspase-3 expression were further explored. Results: Aberrant expression of ABCC3 was an independent factor significantly predicting poor pathological response to neoadjuvant chemoradiotherapy (P=0.002) and prognosis (3-year Overall Survival: P=0.011; 3-year Disease-free Survival: P=0.003). Down-regulation of ABCC3 expression significantly increased 5-fluorouracil or irradiation induced cell apoptosis in vitro, and tumor growth was significantly suppressed following irradiations in vivo. Furthermore, inhibition of ABCC3 expression obviously activated caspase-3 dependent apoptotic pathway and decreased intracellular reactive oxygen species exporting from cells after being exposed to irradiations. Conclusion: ABCC3 is an attractive target for improving sensitivity to neoadjuvant chemoradiotherapy and of potential value for a clinical breakthrough in the comprehensive treatment of rectal cancer patients. Note:This abstract was not presented at the conference. Citation Format: Zhiqi Yu, Chang Zhang, Xianhua Gao, Junjie Xing, Hao Wang, Enda Yu, Wei Zhang, Xiaoqing Zhang, Guangwen Cao, Chuangang Fu. Aberrant expression of ABCC3 in rectal cancer predicts poor prognosis and pathological response to neoadjuvant chemoradiotherapy via activating the caspase-3 dependent apoptotic pathway. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B35.