RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

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.

miR‑182‑5p contributes to radioresistance in nasopharyngeal carcinoma by regulating BNIP3 expression

“…Intensity-modulated radiotherapy (IMRT) is the most prominently used technique for treating patients with NPC. Although IMRT significantly improves the survival rates and local control of NPC in patients, and reduces the toxicity levels ( 1 , 33 – 36 ), radioresistance is the primary cause for the failure of NPC treatment ( 37 ). In the present study, a radioresistant NPC cell model was established, termed 5-8F-R, to identify the key gene and miRNA involved in the acquisition of NPC radioresistance.…”

Properties and gene expression profiling of acquired radioresistance in mouse breast cancer cells

“…We evaluated basal level of ROS and the migration ability in the cells after one radiation schedule (NF639R 40 Gy ) and the cells after two radiation schedule (NF639R). Compared with NF639R 40 Gy cells, NF639R cells displayed enhanced migration ability (Figure 5A,B) and lower basal level of ROS (Figure 5C,D), suggesting that two schedules of radiation (40 Gy/schedule) render NF639R cells more aggressive, Furthermore, we detected the expression of some genes including a positive prognostic indicator (Hoxd13), two inducers of radioresistance (Nqo1 and Aldh3a1) (37,38), one inducer of cell migration (Tgfbi) and two suppressors of cell migration (Sdpr and Klk10) using qPCR in NF639R 40 Gy cells and NF639R cells. The results showed that the expression of Aldh3a1, Tgfbi and Nqo1 were increased, but expression of Sdpr, Klk10 and Hoxd13 were decreased in both NF639R 40 Gy and NF639R cells.…”

Flotillin-2 promotes cell proliferation via activating the c-Myc/BCAT1 axis by suppressing miR-33b-5p in nasopharyngeal carcinoma

“…Western blot was carried out as described previously by us [ 3 , 26 ]. Briefly, the total proteins were collected from RIPA cell lysis by centrifugation.…”

“…Cell proliferation was analyzed using a CCK-8 kit (Beyotime, Shanghai, China) as our previous description [ 3 , 26 ]. The assay was performed three times in triplicate.…”

“…Nasopharyngeal carcinoma (NPC) is one of the most common head and neck cancer, that is highly prevalent in southern China and Southeast Asia [ 1 , 2 ]. Radiation therapy is the primary treatment option, with a high cure rate in early-stage NPC [ 1 , 3 ]. Unfortunately, most NPC patients are diagnosed at advanced stages, characterized by peripheral invasion and lymph node and distant metastasis.…”