Department of Otolaryngology, Central Hospital, Qingdao, Shandong, People's Republic of China.
Department of Otolaryngology, Women and Children's Hospital, Qingdao, Shandong, People's Republic of China.
Drug Des Devel Ther. 2021 Jan 27;15:323-330. doi: 10.2147/DDDT.S292180. eCollection 2021.
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.
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.
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.
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.
耐药性的发展导致许多 NPC 患者在化疗完成后经历疾病复发。因此，阐明这种化疗耐药的机制基础对于确定使 NPC 肿瘤对顺铂和相关药物敏感的方法至关重要。
采用 qRT-PCR 方法测量 NPC 中 circNRIP1 的表达，采用荧光素酶测定法鉴定 circNRIP1 活性的下游靶标包括 miR-515-5p 和 IL-25 的相互作用。还利用 CCK8 测定法检测顺铂和 5-Fu 的 IC50 值。
耐药性 NPC 患者血清中 circNRIP1 的表达明显增加。在功能水平上，我们确定 circNRIP1 能够隔离 miR-515-5p，从而抑制其转录后抑制 IL-25 表达的能力。我们观察到耐药性 NPC 患者血清样本中 miR-515-5p 和 circNRIP1 的表达之间存在显著的负相关，这与这两个因素之间的功能相互作用一致。我们进一步发现，circNRIP1 敲低的 NPC 细胞中 5-Fu 和 CDDP IC50 值在 miR-515-5p 抑制剂转染后恢复。同样，在这些相同的细胞中转染 miR-515-5p 模拟物后，IL-25 过表达会导致这些 IC50 值发生变化，从而逆转这些变化。
这些数据突出了 circNRIP1/miR-515-5p/IL-25 作为 NPC 中 5-Fu 和顺铂耐药的新调节剂，表明该途径可能适合作为治疗这种癌症类型的治疗靶点。
