Abstract:

Objective To analyze the relationship of A2M-induced Fas signaling to drug resistance of ovarian cancer and to patient prognosis. Methods We used gene expression profiles in the Cancer Genome Atlas to search for correlations of A2M expression with drug resistance of ovarian cancer and with patient prognosis based on Pearson correlation analysis. Cisplatin-sensitive or-resistant SKOV3 ovarian cancer cells expressing green fluorescent protein were inoculated subcutaneously into nude mice. At different times after cisplatin administration， tumor tissues were analyzed using real-time fluorescent quantitative PCR to determine expression of A2M and key node genes in the Fas pathway. Correlation between A2M expression and expression of node genes was examined using linear regression. Results A2M correlates significantly with drug resistance of ovarian cancer（P=0.020）. A2M was expressed at significantly lower levels in platinum-resistant tissue than in platinum-sensitive tissue（P<0.05），and higher A2M levels correlated significantly with longer platinum-free interval，overall survival，and progression-free survival（P<0.001）. Platinum-resistant trans-planted tumors expressed significantly lower levels of A2M and the apoptosis-related node genes Fas，FADD，Caspase10， Cas-pase9 and Caspase3 than did platinum-sensitive tumors（P<0.001）. The downstream gene PARP1，important for DNA repair，was expressed at a significantly higher level in platinum-resistant tumors（P< 0.05）. Expression of A2M correlated linearly with that of node genes of the Fas signaling pathway（P<0.05）. Conclusions A2M may be a marker of cisplatin resistance in ovarian cancer. Lower levels of A2M expression may up-regulate expression of the DNA repair protein PARP1， inhibiting cell apoptosis and ultimately leading to cisplatin resistance.

Key words: Ovarian neoplasm, Cisplatin resistance, A2M, Fas signal transduction pathways, The cancer genome atlas