title: CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma.
abstract: BACKGROUND
  In previous investigation, we reported that stably knocking down cyclin-dependent kinase 4(CDK4) induced expression of let-7c, which further suppressed cell cycle transition and cell growth by modulating cell cycle signaling in nasopharyngeal carcinoma (NPC). In this study, we further explored the molecular function and mechanism of CDK4 modulating miRNAs to stimulate cell cycle transition, cell growth, and Cisplatin (DDP) -resistance on in NPC.
  
  
  METHODS
  We identified changes in miRNAs by miRNA array and real-time PCR and the effect on DDP after knocking down CDK4 in NPC cells. Further, we investigated the molecular mechanisms by which CDK4 modulated miR-15a in NPC. Moreover, we also explored the role of miR-15a and the effect on DDP in NPC. Finally, we analyzed the correlation of miR-15a and CDK4 expression in NPC tissues.
  
  
  RESULTS
  In addition to let-7 family members, we observed that upregulated expression of miR-15a was significantly induced in CDK4-suppressed NPC cells. Further, we found that knocking down CDK4 suppressed c-Myc expression, and the latter directly suppressed the expression of miR-15a in NPC. Furthermore, miR-15a as a tumor suppressor antagonized CDK4 repressing cell cycle progression and cell growth in vitro and in vivo and induced the sensitivity of cells to DDP by regulating the c-Myc/CCND1/CDK4/E2F1 pathway in NPC. Finally, miR-15a was negatively weak correlated with the expression of CDK4 in NPC.
  
  
  CONCLUSIONS
  Our studies demonstrate that CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in NPC.
authors.affiliation: Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, P.R. China.|Department of Pathology, Basic School of Guangzhou Medical University, Guangzhou, 510182, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China.|Pediatric Center of Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China.|Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Luo
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Department of Pathology, Basic School of Guangzhou Medical University, Guangzhou, 510182, China.
authors.forename: Yejie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China. longfengxb@126.com.|Otorhinolaryngology of Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, P.R. China. longfengxb@126.com.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Long
authors.affiliation: Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, P.R. China. 413430005@qq.com.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Cancer Research Institute, Southern Medical University, Guangzhou, 510515, China. fangweiyi1975@163.com.|Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China. fangweiyi1975@163.com.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Fang
mesh_terms: D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C505361:MIRN15 microRNA, human; D035683:MicroRNAs; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D002945:Cisplatin
keywords: CDK4; NPC; Tumor suppressor; miR-15a