Interferon regulatory factor-1 suppresses DNA damage response and reverses chemotherapy resistance by downregulating the expression of RAD51 in gastric cancer.
Lulu Tan, Jingsheng Yuan, Wenzhong Zhu, Kaixiong Tao, Guobing Wang, Jinbo Gao
Abstract
Recent studies have shown that IRF-1 plays a significant role in various tumour-induced chemoresistance, but its role and mechanism in gastric cancer-associated chemoresistance are not clear. Our study showed that IRF-1 expression could reverse gastric cancer-related chemoresistance. Dysregulated DNA repair is an important cause of chemoresistance. We established a chemoresistant gastric cancer cell line and found that drug-resistant gastric cancer cells had increased DNA repair ability and that IRF-1 regulated DNA damage repair. Further studies showed that IRF-1 inhibited the expression of RAD51 directly by binding to the RAD51 promoter to affect DNA damage repair; this binding reversed resistance. However, restoring the expression of RAD51 halted the inhibitory effect of IRF-1 partially. Also, we revealed that the overexpression of IRF-1 in a mouse model synergized with chemotherapeutic drugs to inhibit tumour growth. Finally, IRF-1 expression correlated with RAD51 expression in gastric cancer specimens. The expression of IRF-1 and RAD51 are both related to the survival duration of patients with gastric cancer. These results suggest that targeting IRF-1-RAD51 could be an effective approach to reversing multidrug resistance in gastric cancer.