Interferon Regulatory Factor-1 Suppresses the DNA Damage Response and Reverses Chemotherapy Resistance by Downregulating the Expression of RAD51 in Gastric Cancer

Abstract

Recent studies have shown that IRF-1 plays an important role in the chemoresistance of various tumours, but its role and mechanism in the chemoresistance of gastric cancer are not clear. Our study showed that IRF-1 expression could reverse the chemoresistance of gastric cancer. 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 could regulate DNA damage repair. Further study showed that IRF-1 can directly inhibit the expression of RAD51 by binding to the RAD51 promoter to affect DNA damage repair, and this binding can reverse resistance. In addition, we found that overexpression of IRF-1 in a mouse model can synergize with chemotherapeutic drugs to inhibit tumour growth. Moreover, restoring the expression of RAD51 partially rescued the inhibitory effect of IRF-1. Finally, a direct correlation between IRF-1 expression and RAD51 expression was evident 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 indicate that targeting IRF-1-RAD51 may be an effective method for reversing multidrug resistance in gastric cancer. Funding Statement: This work was supported by the National Natural Science Foundation of China (no. 81572411). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: The study and consent procedures were approved by the Institutional Ethics Committee at Huazhong University of Science and Technology. Care and handling of the mice were approved by the Institutional Animal Care and Use Committee of Tongji Medical College, Huazhong University of Science and Technology.