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Down-regulation of miR-26b induces cisplatin resistance in nasopharyngeal carcinoma by repressing JAG1.

ABSTRACT: Therapy against nasopharyngeal carcinoma (NPC) is hurdled by chemoresistance. Recent studies found that microRNA (miRNA) are important regulators of cancer resistance. In this study, we aimed to explore the role and mechanism of miR-26b in regulating NPC cisplatin (CDDP) resistance. Real-time PCR was used to evaluate miR-26b levels in CDDP-resistant and CDDP-sensitive NPC cells, as well as human NPC tissues. MiR-26b was ectopically overexpressed in CDDP-resistant cells, followed by monitoring changes in cell viability and apoptosis. Interaction between JAG1 and miR-26b was characterized by dual-luciferase reporter assay. Furthermore, we investigated whether ectopic JAG1 expression reversed CDDP sensitivity induced by miR-26b overexpression. The effect of FOXD3 down-regulation on miR-26b was also evaluated. Our results indicate that miR-26b was lower in the CDDP-resistant NPC cells, human NPC tissue, particularly in secondary metastases. Ectopic expression of miR-26b sensitized NPC cells to CDDP. JAG1 is a target of miR-26b, and its expression is inversely correlated with miR-26b. Overexpression of JAG1 reversed the CDDP sensitivity induced by miR-26b overexpression. FOXD3 expression was also down-regulated in CDDP-resistant NPC. FOXD3 promoted miR-26b expression and down-regulation of FOXD3 suppressed miR-26b expression. Down-regulation of miR-26b is closely correlated with the CDDP resistance in NPC.

SUBMITTER: Shi L

PROVIDER: S-EPMC5302062 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Down-regulation of miR-26b induces cisplatin resistance in nasopharyngeal carcinoma by repressing JAG1.

Shi Lei L Yin Wei W Zhang Zhiyu Z Shi Guanggang G

FEBS open bio 20161024 12

Therapy against nasopharyngeal carcinoma (NPC) is hurdled by chemoresistance. Recent studies found that microRNA (miRNA) are important regulators of cancer resistance. In this study, we aimed to explore the role and mechanism of miR-26b in regulating NPC cisplatin (CDDP) resistance. Real-time PCR was used to evaluate miR-26b levels in CDDP-resistant and CDDP-sensitive NPC cells, as well as human NPC tissues. MiR-26b was ectopically overexpressed in CDDP-resistant cells, followed by monitoring ch ...[more]

PMID: 28203521

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Project description:OBJECTIVE:To investigate the effect of down-regulation of miR-205-5p on 3-bromopyruvate-induced apoptosis in human nasopharyngeal carcinoma CNE2Z cells. METHODS:Nasopharyngeal carcinoma CNE2Z cells were transfected with miR- 205-5p-mimic or miR-205-5p-inhibitor, treated with 80 ?mol/L 3-bromopyruvate alone, or exposed to both of the treatments. The proliferation of the treated cells was examined with MTT assay, and early apoptosis of the cells was detected using a mitochondrial membrane potential detection kit (JC-1). DAPI fluorescence staining was used to detect morphological changes of the cell nuclei and late cell apoptosis; Annexin V-FITC/PI double staining was employed to detect the cell apoptosis rate. Western blotting was used to detect the expressions of Bcl-2, Bax, Mcl-1 and Bak proteins. RESULTS:Exposure to 3-bromopyruvate significantly inhibited the proliferation of CNE2Z cells, and increasing the drug concentration and extending the treatment time produced stronger inhibitory effects. Treatment with 80 ?mol/L 3-bromopyruvate for 24, 48 and 72 h resulted in inhibition rates of (45.7±1.21)%, (64.4±2.02)% and (78.3±1.55)% in non-transfected CNE2Z cells, respectively; the inhibition rates were (27.7±1.04)%, (34.8±2.10)% and (44.3±1.57)% in the cells transfected with miR-205-5p-mimic, and were (80.5 ± 0.94)%, (87.9 ± 0.50)% and (93.8 ± 1.16)% in cells transfected with miR-205-5p-inhibitor, respectively. The results of mitochondrial membrane potential detection showed that the relative proportion of red and green fluorescence decreased significantly in miR-205-5p-inhibitor-transfected cells with 3-bromopyruvate treatment. Combined treatment of the cells with 3-bromopyruvate and miR-205-5p-inhibitor transfection obviously increased nuclear fragmentation and nuclear pyknosis and significantly increased cell apoptotic rate as compared with the two treatments alone (P < 0.01), causing also decreased expressions of Bcl-2 and Mcl-1 proteins and increased expressions of Bax and Bak proteins. CONCLUSIONS:Inhibition of miR-205-5p enhances the proapototic effect of 3-bromopyruvate in CNE2Z cells possibly in relation to the down-regulation of Mcl-1 and Bcl-2 and the up-regulation of Bak and Bax proteins.

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Down-regulation of miR-26b induces cisplatin resistance in nasopharyngeal carcinoma by repressing JAG1.

Publications

Down-regulation of miR-26b induces cisplatin resistance in nasopharyngeal carcinoma by repressing JAG1.

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