Qi Wang,MengdiLi, Hongmei liu, Jie Shu, Li Li

Key laboratory of high incidence of tumors of theGuangxi region, ministry of education, Affiliated cancer hospital of Guangximedical university

Objective:Platinum-resistant play an important roleof poor prognosis in ovarian cancer. Cellular retinoic acid-binding protein2(CRABP2) were considered the potential upstream molecules for inhibitingplatinum-resistant by using an integrative analysis of system biology andclinical data. The aim of this study was to describe the relationship betweenCRABP2 and prognostic factors of patients with epithelial ovarian cancer (EOC).Moreover, the downstream signaling pathways of CRABP2 were investigated tounderstand molecular mechanism of platinum-resistant reverse in vivo and vitro. Method: We retrospectively analyzed the clinical recordsof 289 patients with EOC treated by platinum chemotherapy. The expression ofCRABP2 was evaluated real-time fluorescence quantitative. Progression freesurvival (FPS) and overall survival (OS) curves were calculated by the Kaplan-Meiermethod. We used the multivariate analysis to assess the possible prognosticindicators for survival, including age, stage, grade, tumor residual disease,primary therapy outcome, platinum status. In addition, CRABP2 wasover-expressed to Skov3 cell lines with cisplatin resistant, and theninoculated into nude mice to develop implantation tumor model. The IC50 of celland related proteins of Fas pathway were detected in cell line and xenograftsafter treat with cisplatin. Result:  Higher Patients with highCRABP2 expression had significantly better PFS (P<0.001) and OS (P<0.001)than patients with low CRABP2 expression Cox regression analysis showed thatCRABP2scan be regarded as the independent prognostic indicators. IC50 withcisplatin of the CRABP2-overexpressed SKOV3 cell line are significantly lowerthan the control SKOV3 (P<0.00). Proteins of cell apoptosis, such asFas, FADD, Caspase10, Caspase9 and Caspase3 were significantly higher in thexenografts with the cisplatin injection (P<0.00), while itsdownstream targeted gene PARP1, which is very important to cell DNA repair, isdown-regulated in the CRABP2-overexpressed tumor tissues (P<0.05). Conclusion:CRABP2 are was strongly associated with platinum resistance of EOC. CRABP2may be a potential upstream gene of the platinum resistance by activating theFas apoptosis signaling pathways, which provides new molecule forchemo-resistance reverse.

Key Words: Platinum resistant, Epithelial ovarian cancer