title: PinX1 suppresses bladder urothelial carcinoma cell proliferation via the inhibition of telomerase activity and p16/cyclin D1 pathway.
abstract: BACKGROUND
  PIN2/TRF1-interacting telomerase inhibitor1 (PinX1) was recently suggested as a putative tumor suppressor in several types of human cancer, based on its binding to and inhibition of telomerase. Moreover, loss of PinX1 has been detected in many human malignancies. However, the possible involvement of PinX1 and its clinical/prognostic significance in urothelial carcinoma of the bladder (UCB) are unclear.
  
  
  METHODS
  The PinX1 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC) in UCB tissues and adjacent normal urothelial bladder epithelial tissues. PinX1 was overexpressed and silenced in UCB cell lines to determine its role in tumorigenesis, development of UCB, and the possible mechanism.
  
  
  RESULTS
  PinX1 expression in UCB was significantly down-regulated at both mRNA and protein level as compared with that in normal urothelial bladder epithelial tissues. PinX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index (Ki-67), and poor survival (P < 0.05). Moreover, overexpression of PinX1 in UCB cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing PinX1 dramatically enhanced cell proliferation. Overexpression of PinX1 resulted in G1/S phase arrest and cell growth/proliferation inhibition, while silencing PinX1 led to acceleration of G1/S transition, and cell growth/proliferation promotion by inhibiting/enhancing telomerase activity and via the p16/cyclin D1 pathway.
  
  
  CONCLUSIONS
  These findings suggest that down-regulation of PinX1 play an important role in the tumorigenesis and development of UCB and that the expression of PinX1 as detected by IHC is an independent molecular marker in patients with UCB.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No, 651, Dongfeng Road East, Guangzhou 510060, China. zhoufj@sysucc.org.cn.
authors.forename: Jian-Ye
authors.initials: JY
authors.lastname: Liu
authors.forename: Dong
authors.initials: D
authors.lastname: Qian
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: He
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Yi-Ji
authors.initials: YJ
authors.lastname: Liao
authors.forename: Shi-Juan
authors.initials: SJ
authors.lastname: Mai
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Tian
authors.forename: Yan-Hui
authors.initials: YH
authors.lastname: Liu
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Zhang
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Fang-Jian
authors.initials: FJ
authors.lastname: Zhou
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
mesh_terms: D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D016016:Proportional Hazards Models; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism*; D059505:Telomere Homeostasis; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology
chemical_list: C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C440808:PINX1 protein, human; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C509186:TERT protein, human; D019098:Telomerase