Abstract
Dysregulation of RKIP and NRF2 has been widely involved in the therapy resistance of multiple malignances, however, their relation and the corresponding mechanisms, especially in radiation response, have not been elucidated. In this study, we revealed that RKIP could negatively regulate the expression of NRF2 in nasopharyngeal carcinoma (NPC) cells. Depletion or ectopic expression of NRF2 countered the pro- or anti- radioresistant effects of RKIP knockdown or overexpression on NPC cells, respectively, both in vitro and in vivo. Furthermore, our results indicated that NQO1 was positively regulated by NRF2 and served as the downstream effector of RKIP/NRF2 axis in regulation of NPC radioresistance. Mechanistically, miR-450b-5p, being positively regulated by RKIP in NPC cells, could sensitize NPC cells to irradiation by directly targeting and suppressing the level of NRF2. Besides, we analyzed the level of aforementioned molecules in NPC tissues. The results indicated that RKIP was significantly downregulated, NRF2 and NQO1 were notably upregulated in NPC tissues compared with in normal nasopharyngeal mucosa (NNM) tissues. Furthermore, RKIP and miR-450b-5p were remarkably lower, yet NRF2 and NQO1 were notably higher, in radioresistant NPC tissues relative to in radiosensitive NPC tissues. Consistent with the pattern in NPC cells, the RKIP/miR-450b-5p/NRF2/NQO1 axis was significantly correlated in NPC tissues. Downregulation of RKIP and miR-450b-5p, and upregulation of NRF2 and NQO1, positively correlated to malignant pathological parameters such as primary T stage, Lymph node (N) metastasis, and TNM stage. Finally, RKIP and miR-450b-5p served as favorable prognostic indicators, and NRF2 and NQO1 acted as unfavorable prognostic biomarkers in patients with NPC. Collectively, our outcomes reveal that RKIP downregulation promotes radioresistance of NPC by downregulating miR-450b-5p and subsequently upregulating and activating NRF2 and NQO1, highlighting RKIP/miR-450b-5p/NRF2/NQO1 axis as a potential therapeutic target for improving the radiosensitivity of NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is one of most prevalent head and neck cancers in the middle and southeast coastal regions of China
These results indicated that Raf kinase inhibitor protein (RKIP) could inversely regulate NRF2 level in NPC cells with district radiosensitivity in an independent manner with Keap[1], indicating NRF2 may play an important role in RKIP regulated radioresistance in NPC
We further revealed that RKIP could negatively regulated NRF2/NQO1 activity and enhanced the nasopharyngeal mucosa (NNM) Radiosensitive NPC Radioresistant NPC
Summary
Nasopharyngeal carcinoma (NPC) is one of most prevalent head and neck cancers in the middle and southeast coastal regions of China. Overwhelming reactive oxidative stress (ROS), induced by irradiation, is one of big challenges for survival of cancer cells[4]. Upregulation of genes/proteins with ROS removal capability seem to be the obliged choice for cancer cells to maintain survival. (Nuclear factor erythroid 2-related factor 2), one of basic leucine zipper transcription factors, which serves as an essential activator of genes encoding antioxidant enzymes and phases II detoxifying enzymes such as HO-1 (Heme oxygenase-1), NQO1 (NAD(P)H dehydrogenase, quinone 1), PRDX1(Peroxiredoxin1), and GCLC (glutamate-cystine ligase catalytic subunit)[5], is upregulated or activated in various radioresistant cancer cells, including lung cancer[6,7], alveolar rhabdomyosarcoma[8], hepatoma[9], and breast cancer[10]. The activity of NRF2 is regulated by both
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