title: Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion.
abstract: Urothelial carcinoma associated 1 (UCA1) has been identified as an oncogenic long noncoding RNA (lncRNA) that is involved in bladder cancer progression and acts as a diagnostic biomarker for bladder carcinoma. Here, we studied the expression and function of lncRNA-UCA1 in the hypoxic microenvironment of bladder cancer. The expression and transcriptional activity of lncRNA-UCA1 were measured by quantitative real-time polymerase chain reaction and luciferase assays. Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry. Cell migration and invasion were detected by wound healing, migration, and invasion assays. The binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the lncRNA-UCA1 promoter was confirmed by electrophoretic mobility shift assay and chromatin immunoprecipitation. HRE mutations were generated by using a site-directed mutagenesis kit, and HIF-1α knockdown was mediated by small interfering RNA. The effect of HIF-1α inhibition by YC-1 on lncRNA-UCA1 expression was also examined. LncRNA-UCA1 was upregulated by hypoxia in bladder cancer cells. Under hypoxic conditions, lncRNA-UCA1 upregulation increased cell proliferation, migration, and invasion and inhibited apoptosis. The underlying mechanism of hypoxia-upregulated lncRNA-UCA1 expression was that HIF-1α specifically bound to HREs in the lncRNA-UCA1 promoter. Furthermore, HIF-1α knockdown or inhibition could prevent lncRNA-UCA1 upregulation under hypoxia. These findings revealed the mechanism of lncRNA-UCA1 upregulation in hypoxic bladder cancer cells and suggested that effective blocking of lncRNA-UCA1 expression in the hypoxic microenvironment of bladder cancer could be a novel therapeutic strategy.
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Peoples Republic of China.
authors.forename: Mei
authors.initials: M
authors.lastname: Xue
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.forename: Zhengkun
authors.initials: Z
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D062085:RNA, Long Noncoding; C515159:UCA1 RNA, human
references.citation: Nat Rev Cancer. 2003 Oct;3(10):721-32
references.pmid: 13130303
references.citation: Cell. 2007 May 4;129(3):465-72
references.pmid: 17482542
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D983-6
references.pmid: 23175614
references.citation: Biochem Pharmacol. 2013 May 1;85(9):1278-87
references.pmid: 23416116
references.citation: J Clin Invest. 2010 Nov;120(11):3815-7
references.pmid: 20972325
references.citation: RNA Biol. 2012 Jun;9(6):703-19
references.pmid: 22664915
references.citation: Bioinformatics. 2005 Jul 1;21(13):2933-42
references.pmid: 15860560
references.citation: FEBS Lett. 2008 Jun 11;582(13):1919-27
references.pmid: 18501714
references.citation: Science. 2001 Apr 20;292(5516):468-72
references.pmid: 11292861
references.citation: Drug Resist Updat. 2007 Feb-Apr;10(1-2):13-29
references.pmid: 17303468
references.citation: PLoS One. 2007 Sep 05;2(9):e845
references.pmid: 17786216
references.citation: Cell Death Differ. 2008 Apr;15(4):678-85
references.pmid: 18259193
references.citation: Oncogene. 2013 Aug 29;32(35):4057-63
references.pmid: 23222717
references.citation: Tumour Biol. 2013 Aug;34(4):2019-30
references.pmid: 23686802
references.citation: PLoS One. 2013 Sep 12;8(9):e73920
references.pmid: 24069250
references.citation: Science. 2012 Dec 14;338(6113):1435-9
references.pmid: 23239728
references.citation: Cell. 2010 Oct 1;143(1):46-58
references.pmid: 20887892
references.citation: Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
references.pmid: 7539918
references.citation: Gastroenterology. 2007 Jan;132(1):330-42
references.pmid: 17241883
references.citation: Cell. 2001 Oct 5;107(1):1-3
references.pmid: 11595178
references.citation: Mol Cell. 2013 Mar 28;49(6):1083-96
references.pmid: 23395002
references.citation: CA Cancer J Clin. 2010 Jul-Aug;60(4):244-72
references.pmid: 20566675
references.citation: Mol Cancer. 2013 Sep 05;12(1):101
references.pmid: 24006935
references.citation: Int J Cancer. 2014 Apr 15;134(8):1776-84
references.pmid: 24122582
references.citation: Biochim Biophys Acta. 2010 Apr;1803(4):443-51
references.pmid: 20117150
references.citation: Urol Int. 2012;88(1):95-101
references.pmid: 22041818
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D105-10
references.pmid: 19906716
references.citation: Mol Cell. 2010 Oct 22;40(2):294-309
references.pmid: 20965423
references.citation: Mol Cell. 2014 Jan 9;53(1):88-100
references.pmid: 24316222
references.citation: Urol Oncol. 2012 Nov-Dec;30(6):928-35
references.pmid: 22341926
references.citation: J Cell Biochem. 2009 Aug 15;107(6):1053-62
references.pmid: 19479945
references.citation: Lab Invest. 2010 Oct;90(10):1406-14
references.pmid: 20661228
references.citation: Eur Urol. 2004 Aug;46(2):200-8
references.pmid: 15245814
references.citation: Gene. 2012 Mar 15;496(1):8-16
references.pmid: 22285928
references.citation: Nat Rev Clin Oncol. 2011 Mar;8(3):129-30
references.pmid: 21283126