title: Knocking down CDK4 mediates the elevation of let-7c suppressing cell growth in nasopharyngeal carcinoma.
abstract: BACKGROUND
  CDK4 is a protein kinase in the CDK family important for G1/S phase cell cycle progression. However, the roles and molecular mechanisms of CDK4 triggering nasopharynx carcinogenesis are still unclear.
  
  
  METHODS
  Lentiviral-vector mediated shRNA was used to suppress CDK4 expression and examine its molecular mechanisms. Using immunohistochemistry, we analyzed CDK4 protein expression in clinicopathologically characterized nasopharyngeal carcinoma (NPC) cases and nasopharyngeal tissues (NPs). Survival curves were plotted by the Kaplan-Meier method and compared using the log-rank test.
  
  
  RESULTS
  In this investigation, we knocked down CDK4 expression and observed that NPC cell growth and cell cycle progression were significantly blocked by suppressing expression of CCND1, CDK6, and E2F1 as well as elevated p21 expression. Further, we found that reduced CDK4 expression elevated the expression of let-7c, a tumor-suppressive miRNA modulated by E2F1. We found that let-7c was markedly downregulated in NPC tissues compared to NPs and suppressed cell growth and cell cycle progression by modulating p15/p16/CDK4/E2F1 pathway. Finally, CDK4 protein was observed to be overexpressed in NPC tissues and could be considered an unfavorable prognosis factor for NPC patients although its independent prognostic value did not reach statistical significance (p = 0.087).
  
  
  CONCLUSIONS
  Our results demonstrated that overexpressed CDK4 is an unfavorable prognostic factor which suppresses the expression of tumor suppressive-factor let-7c through p21/CCND1/CDK6/E2F1 signaling, and inhibits cell proliferation by p15/p16/CDK4/E2F1 feedback signaling in NPC.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Long
authors.forename: Cheng
authors.initials: C
authors.lastname: Chao
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Qiangyun
authors.initials: Q
authors.lastname: Wu
authors.forename: Shengni
authors.initials: S
authors.lastname: Hua
authors.affiliation: Department of Pathology, Guangzhou Medical University, Guangzhou 510182, China. yajie.zhang@163.com.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Aibing
authors.initials: A
authors.lastname: Wu
authors.forename: Weiyi
authors.initials: W
authors.lastname: Fang
mesh_terms: D002277:Carcinoma; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4
references.citation: J Transl Med. 2011 Apr 11;9:38
references.pmid: 21477379
references.citation: Am J Pathol. 2002 Aug;161(2):405-11
references.pmid: 12163365
references.citation: Cell Death Dis. 2010 Nov 04;1:e94
references.pmid: 21368870
references.citation: BMC Cancer. 2010 Nov 06;10:610
references.pmid: 21054888
references.citation: J Biol Chem. 2012 Jan 6;287(2):1527-37
references.pmid: 22128178
references.citation: Neuroendocrinology. 2007;86(2):112-8
references.pmid: 17664862
references.citation: J Natl Cancer Inst. 2012 Sep 19;104(18):1396-410
references.pmid: 22972969
references.citation: Int J Cancer. 2007 Jul 1;121(1):66-75
references.pmid: 17304504
references.citation: Cell Death Dis. 2012 Jul 19;3:e351
references.pmid: 22825469
references.citation: J Pathol. 2013 Jul;230(3):336-46
references.pmid: 23592276
references.citation: BMC Cancer. 2012 Jul 28;12:321
references.pmid: 22839099
references.citation: Cell Death Dis. 2013 Oct 24;4:e872
references.pmid: 24157866
references.citation: Nat Cell Biol. 2003 Jul;5(7):655-60
references.pmid: 12833065
references.citation: J Cell Mol Med. 2009 Sep;13(9B):3906-17
references.pmid: 18624766
references.citation: J Oral Pathol Med. 2010 Nov;39(10):793-9
references.pmid: 20618617
references.citation: Cell Death Dis. 2010 Oct 21;1:e85
references.pmid: 21368858
references.citation: Zhonghua Gan Zang Bing Za Zhi. 2011 Nov;19(11):853-6
references.pmid: 22433309
references.citation: Cancer Res. 2006 Jan 15;66(2):693-700
references.pmid: 16423998
references.citation: J Cell Mol Med. 2009 Sep;13(9A):2843-52
references.pmid: 18624751
references.citation: Mol Cancer. 2013 Oct 24;12(1):128
references.pmid: 24156782
references.citation: Blood. 1995 Oct 15;86(8):2900-5
references.pmid: 7579381
references.citation: Oncogene. 2004 Mar 11;23(10):1863-73
references.pmid: 14647432
references.citation: PLoS One. 2012;7(3):e32832
references.pmid: 22479342
references.citation: BMC Cancer. 2013 Mar 27;13:157
references.pmid: 23530816
references.citation: Genes Chromosomes Cancer. 2005 Feb;42(2):193-9
references.pmid: 15543620
references.citation: BMC Cancer. 2007 Jan 29;7:22
references.pmid: 17261172
references.citation: J Int Med Res. 2011;39(6):2323-9
references.pmid: 22289550
references.citation: Int J Cancer. 2004 Jul 1;110(4):532-41
references.pmid: 15122585
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Mod Pathol. 2010 Sep;23(9):1279-88
references.pmid: 20601938
references.citation: Cell Death Dis. 2013 May 16;4:e634
references.pmid: 23681229
references.citation: J Cell Mol Med. 2012 Sep;16(9):2208-18
references.pmid: 22260183
references.citation: Cancer Causes Control. 2012 Dec;23(12):1995-2002
references.pmid: 23085811
references.citation: J Transl Med. 2008 Jun 20;6:32
references.pmid: 18570662