Reduction of microRNA-184 by E6 oncoprotein confers cisplatin resistance in lung cancer via increasing Bcl-2
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Min-Che Tung1,3,*, Po-Lin Lin4,*, Ya-Wen Cheng2, De-Wei Wu2, Sauh-Der Yeh1, Chi-Yi Chen5, Huei Lee2
1Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
2Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
3Department of Surgery, Tung’s Taichung Metro-Harbor Hospital, Taichung, Taiwan
4Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
5Department of Surgery, Chung Shan Medical University, Taichung, Taiwan
*These authors contributed equally to this work
Huei Lee, email: email@example.com
Keywords: miR-184, HPV, cisplatin resistance
Received: November 02, 2015 Accepted: March 28, 2016 Published: April 12, 2016
MicroRNA-184 suppresses cell growth and survival via targeting c-Myc and Bcl- 2. We recently reported that miR-184 promotes tumor progression in non-small cell lung cancer via targeting CDC25A and c-Myc. We here hypothesized that miR-184 could be down-regulated by E6 oncoprotein to confer cisplatin resistance in NSCLC. Human papillomavirus (HPV) 16-positive lung cancer TL-1 and cervical cancer SiHa cells compared with HPV16-negative TL-10 and C33A cells were enrolled for E6 manipulation. MiR-184 expression levels were increased by E6-knockdown in TL-1 and SiHa cells, but decreased by E6-overexpression in TL-10 and C33A cells. The MTT assay showed that the inhibition concentration of cisplatin yielding for 50% cell viability was dependent on miR-184 levels. Bcl-2 de-targeted by E6-mediated miR- 184 reduction was responsible for cisplatin resistance. Luciferase reporter assay and real- time PCR analysis indicated that the miR-184 promoter activity and its expression were modulated by E6 and/or p53 manipulation. Chromatin immunoprecipitation (ChIP) assay confirmed that p53 was bound onto the miR-184 promoter and its binding activity was modulated by E6 and/or p53 manipulation. Among patients, high miR184 and high Bcl-2 mRNA expression was more commonly occurred in E6- positive tumors than in E6-negative tumors. Fifty-nine out of 136 patients receiving cisplatin-based chemotherapy were available for the retrospective study. Patients with low-mR-184, E6-positive, high-Bcl-2 tumors, and both combinations were more prevalently occurred unfavorable response to cisplatin-based chemotherapy than their counterparts. In conclusion, a decrease in miR-184 level by E6 oncoprotein may predict unfavorable response to cisplatin-based chemotherapy in HPV-infected NSCLC patients via increasing Bcl-2 expression.
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