MiR-125b Increases Nasopharyngeal Carcinoma Radioresistance by Targeting A20/NF-κB Signaling Pathway

Abstract

Radioresistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, but little is known about how miRNA regulates this phenomenon. In this study, we investigated the function and mechanism of miR-125b in NPC radioresistance, one of upregulated miRNAs in the radioresistant NPC cells identified by our previous microarray analysis. We observed that miR-125b was frequently upregulated in the radioresistant NPCs, and its increment was significantly correlated with NPC radioresistance, and was an independent predictor for poor patient survival. radioresponse assays showed that miR-125b inhibitor decreased, whereas miR-125b mimic increased NPC cell radioresistance. In a mouse model, therapeutic administration of miR-125b antagomir dramatically sensitized NPC xenografts to irradiation. Mechanistically, we confirmed that A20 was a direct target of miR-125b and found that miR-125b regulated NPC cell radioresponse by targeting A20/NF-κB signaling. With a combination of loss-of-function and gain-of-function approaches, we further showed that A20 overexpression decreased while A20 knockdown increased NPC cell radioresistance both and Moreover, A20 was significantly downregulated while p-p65 (RelA) significantly upregulated in the radioresistant NPCs relative to radiosensitive NPCs, and miR-125b expression level was negatively associated with A20 expression level, whereas positively associated with p-p65 (RelA) level. Our data demonstrate that miR-125b and A20 are critical regulators of NPC radioresponse, and high miR-125b expression enhances NPC radioresistance through targeting A20 and then activating the NF-κB signaling pathway, highlighting the therapeutic potential of the miR-125b/A20/NF-κB axis in clinical NPC radiosensitization..

MicroRNA‑212 suppresses cell proliferation in nasopharyngeal carcinoma by targeting ELF3

“…A number of studies have reported that miRNAs can serve roles as tumor suppressors and oncogenes. Aberrant expression levels of miRNAs and genes have been detected in NPC in a number of studies; several miRNAs are upregulated in NPC, including miR-27a-3p (21), miR-93 (22) and miR-125b (23), and certain miRNAs are downregulated in NPC, including miR-135a (10), miR-203a-3p (12) and miR-185 (24). The present study demonstrated that the expression levels of miR-212 were significantly lower in NPC tissues and cell lines compared with normal controls.…”

Effects of microRNA‑125b on multiple myeloma cell growth in vitro and in vivo

“…Notably, miR-125b belongs to the miR-17-92 cluster and has been reported to act as an oncogene in several human malignancies. Wang et al demonstrated that miR-125b was overexpressed in nasopharyngeal carcinoma (32). Shen et al reported that the expression of miR-125b was markedly increased in type II diabetes mellitus (33).…”

MiRNAs in Radiotherapy Resistance of Nasopharyngeal Carcinoma

“…Inactivation of PTEN results in constitutive activation of the STAT3 and PI3K-AKT pathways and subsequent protein synthesis, inhibiting apoptosis. Experiments have shown that Bcl-2 protein levels are increased in miR-205 transfected CNE-2 cells, and studies have shown that STAT3 activation can inhibit cell apoptosis by blocking the expression of Bim protein [50,51]. However, miR-185, which enhances apoptosis, can increase the expression of Bax and Bid and decrease the expression of Bcl-2, promoting apoptosis, [52].…”