CircNRIP1 Modulates the miR-515-5p/IL-25 Axis to Control 5-Fu and Cisplatin Resistance in Nasopharyngeal Carcinoma

BACKGROUND: The development of drug resistance leads many NPC patients to experience disease relapse following the completion of chemotherapy. It is thus essential that the mechanistic basis for such chemoresistance be clarified in an effort to identify approaches to sensitizing NPC tumors to treatment with cisplatin and related agents. METHODS: A qRT-PCR approach was used to measure the expression of circNRIP1 in NPC, while luciferase assays were used to identify interactions with downstream targets of circNRIP1 activity including miR-515-5p and IL-25. CCK8 assays were also utilized to detect IC50 values for cisplatin and 5-Fu. RESULTS: The expression of circNRIP1 was significantly increased in the serum of chemoresistant NPC patients. At a functional level, we determined that circNRIP1 is able to sequester miR-515-5p, thereby inhibiting its ability to post-transcriptionally suppress IL-25 expression. We observed a significant negative correlation between the expression of miR-515-5p and circNRIP1 in serum samples from chemoresistant NPC patients, consistent with a functional interaction between these two factors. We further found that 5-Fu and CDDP IC50 values in NPC cells in which circNRIP1 had been knocked down were restored following miR-515-5p inhibitor transfection. Similarly, changes in these IC50 values were reversed in NPC cells transfected with miR-515-5p mimics following the overexpression of IL-25 in these same cells. CONCLUSION: These data highlight the circNRIP1/miR-515-5p/IL-25 as a novel regulator of 5-Fu and cisplatin resistance in NPC, suggesting that this pathway may be amenable to therapeutic targeting as an approach to treating this cancer type.