Abstract C217: Prognostic significance and molecular mechanism of ATP-Binding Cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma.

Abstract

Abstract Mechanism of radioresistance in rectal carcinoma remains largely unknown. The aim of this study is to verify the predictive value of ATP-Binding Cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy. Methods: Expression of ABCC4 protein in pretreated biopsy tissue specimens from locally advanced rectal carcinoma patients was examined using immunohistochemistry. The 3-year overall survival and disease-free survival were used to determine long-term prognosis, and significant clinicopathological factors were identified by univariate log-rank test and multivariate Cox regression analysis. Lentivirus-mediated small hairpin RNA inhibited ABCC4 expression in colorectal carcinoma cell lines, and altered radiosensitivity was confirmed by xenograft model in vivo. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were further detected. Results: High expression of ABCC4 in pretreated tumors, p53 mutant type, high serum CEA and positive lymph node predicted an unfavorable postoperative prognosis for locally advanced rectal carcinoma patients after neoadjuvant radiotherapy in univariate analysis. Multivariate Cox regression analysis further demonstrated that high expression of ABCC4 and p53 mutant type were significant factors independently predicted an unfavorable long-term prognosis. Downregulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model in vivo. Furthermore, inhibition of ABCC4 expression induced intracellular cyclic adenosine monophosphate accumulation and a noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation. Conclusions: Our study suggests ABCC4 as a novel predictive biomarker in predicting radioresistance and prognosis for locally advanced rectal carcinoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C217. Citation Format: Zhiqi Yu, Chang Zhang, Rui Chai, Yan Du, Xianhua Gao, Junjie Xing, Guangwen Cao, Chuangang Fu. Prognostic significance and molecular mechanism of ATP-Binding Cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C217.