Top

Published in:

01-07-2014 | Research Article

Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion

Authors: Mei Xue, Xu Li, Zhengkun Li, Wei Chen

Published in: Tumor Biology | Issue 7/2014

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.

Available only for authorised users

Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107(6):1053–62. doi:10.1002/jcb.22214.CrossRefPubMed

Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension. Proc Natl Acad Sci U S A. 1995;92(12):5510–4.PubMedCentralCrossRefPubMed

Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O₂-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72. doi:10.1126/science.1059796.CrossRefPubMed

Semenza GL. HIF-1, O₂, and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001;107(1):1–3.CrossRefPubMed

Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40(2):294–309. doi:10.1016/j.molcel.2010.09.022.PubMedCentralCrossRefPubMed

Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129(3):465–72. doi:10.1016/j.cell.2007.04.019.PubMedCentralCrossRefPubMed

Jacobs BL, Lee CT, Montie JE. Bladder cancer in 2010: how far have we come? CA Cancer J Clin. 2010;60(4):244–72. doi:10.3322/caac.20077.CrossRefPubMed

Gospodarowicz M. Combination therapy: hypoxia modification with radiotherapy for bladder cancer. Nat Rev Clin Oncol. 2011;8(3):129–30. doi:10.1038/nrclinonc.2011.5.CrossRefPubMed

Theodoropoulos VE, Lazaris A, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, et al. Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol. 2004;46(2):200–8. doi:10.1016/j.eururo.2004.04.008.CrossRefPubMed

10.

Chen MC, Lee CF, Huang WH, Chou TC. Magnolol suppresses hypoxia-induced angiogenesis via inhibition of HIF-1alpha/VEGF signaling pathway in human bladder cancer cells. Biochem Pharmacol. 2013;85(9):1278–87. doi:10.1016/j.bcp.2013.02.009.CrossRefPubMed

11.

Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, et al. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010;143(1):46–58.PubMedCentralCrossRefPubMed

12.

Lee JT. Epigenetic regulation by long noncoding RNAs. Science. 2012;338(6113):1435–9.CrossRefPubMed

13.

Gutschner T, Diederichs S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 2012;9(6):703–19. doi:10.4161/rna.20481.PubMedCentralCrossRefPubMed

14.

Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology. 2007;132(1):330–42. doi:10.1053/j.gastro.2006.08.026.CrossRefPubMed

15.

Wang F, Li X, Xie X, Zhao L, Chen W. UCA1, a non-protein-coding RNA up-regulated in bladder carcinoma and embryo, influencing cell growth and promoting invasion. FEBS Lett. 2008;582(13):1919–27. doi:10.1016/j.febslet.2008.05.012.CrossRefPubMed

16.

Chen G, Wang Z, Wang D, Qiu C, Liu M, Chen X, et al. LncRNADisease: a database for long-non-coding RNA-associated diseases. Nucleic Acids Res. 2013;41(Database issue):D983–6. doi:10.1093/nar/gks1099.PubMedCentralCrossRefPubMed

17.

Zhang Q, Su M, Lu G, Wang J. The complexity of bladder cancer: long noncoding RNAs are on the stage. Mol Cancer. 2013;12(1):101. doi:10.1186/1476-4598-12-101.PubMedCentralCrossRefPubMed

18.

Loscalzo J. The cellular response to hypoxia: tuning the system with microRNAs. J Clin Invest. 2010;120(11):3815–7. doi:10.1172/JCI45105.PubMedCentralCrossRefPubMed

19.

Yang C, Li X, Wang Y, Zhao L, Chen W. Long non-coding RNA UCA1 regulated cell cycle distribution via CREB through PI3-K dependent pathway in bladder carcinoma cells. Gene. 2012;496(1):8–16. doi:10.1016/j.gene.2012.01.012.CrossRefPubMed

20.

Wu W, Zhang S, Li X, Xue M, Cao S, Chen W. Ets-2 regulates cell apoptosis via the Akt pathway, through the regulation of urothelial cancer associated 1, a long non-coding RNA, in bladder cancer cells. PLoS ONE. 2013;8(9):e73920. doi:10.1371/journal.pone.0073920.PubMedCentralCrossRefPubMed

21.

Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A, et al. MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics. 2005;21(13):2933–42. doi:10.1093/bioinformatics/bti473.CrossRefPubMed

22.

Portales-Casamar E, Thongjuea S, Kwon AT, Arenillas D, Zhao X, Valen E, et al. JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles. Nucleic Acids Res. 2010;38(Database issue):D105–10. doi:10.1093/nar/gkp950.PubMedCentralCrossRefPubMed

23.

Ching CB, Hansel DE. Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway. Lab Invest. 2010;90(10):1406–14. doi:10.1038/labinvest.2010.133.CrossRefPubMed

24.

Calderaro J, Rebouissou S, de Koning L, Masmoudi A, Herault A, Dubois T, et al. PI3K/AKT pathway activation in bladder carcinogenesis. Int J Cancer. 2014;134(8):1776–84. doi:10.1002/ijc.28518.CrossRefPubMed

25.

Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Zuse A, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat. 2007;10(1–2):13–29. doi:10.1016/j.drup.2007.01.003.CrossRefPubMed

26.

Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, et al. The H19 non-coding RNA is essential for human tumor growth. PLoS ONE. 2007;2(9):e845. doi:10.1371/journal.pone.0000845.PubMedCentralCrossRefPubMed

27.

Matouk IJ, Mezan S, Mizrahi A, Ohana P, Abu-Lail R, Fellig Y, et al. The oncofetal H19 RNA connection: hypoxia, p53 and cancer. Biochim Biophys Acta. 2010;1803(4):443–51. doi:10.1016/j.bbamcr.2010.01.010.CrossRefPubMed

28.

Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F, et al. Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 2013;49(6):1083–96. doi:10.1016/j.molcel.2013.01.010.CrossRefPubMed

29.

Yang F, Zhang H, Mei Y, Wu M. Reciprocal regulation of HIF-1alpha and lincRNA-p21 modulates the Warburg effect. Mol Cell. 2014;53(1):88–100. doi:10.1016/j.molcel.2013.11.004.CrossRefPubMed

30.

Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15(4):678–85. doi:10.1038/cdd.2008.21.PubMedCentralCrossRefPubMed

31.

Fazilaty H, Gardaneh M, Bahrami T, Salmaninejad A, Behnam B. Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? Tumour Biol. 2013;34(4):2019–30. doi:10.1007/s13277-013-0831-y.CrossRefPubMed

32.

Semenza GL. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene. 2013;32(35):4057–63. doi:10.1038/onc.2012.578.PubMedCentralCrossRefPubMed

33.

Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32. doi:10.1038/nrc1187.CrossRefPubMed

34.

Zhang T, Fan J, Wu K, Zeng J, Sun K, Guan Z, et al. Roles of HIF-1alpha in a novel optical orthotopic spontaneous metastatic bladder cancer animal model. Urol Oncol. 2012;30(6):928–35. doi:10.1016/j.urolonc.2012.01.003.CrossRefPubMed

35.

Li Y, Zhao X, Tang H, Zhong Z, Zhang L, Xu R, et al. Effects of YC-1 on hypoxia-inducible factor 1 alpha in hypoxic human bladder transitional carcinoma cell line T24 cells. Urol Int. 2012;88(1):95–101. doi:10.1159/000331881.CrossRefPubMed

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
Authors: Mei Xue
Xu Li
Zhengkun Li
Wei Chen
Publication date: 01-07-2014
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 7/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-014-1925-x

2024 ASCO Annual Meeting Coverage

Highlights of the Day: Breast cancer – metastatic

Breast Cancer Video

In this session, Dr. Wolff provides his key takeaways from the data presented in the metastatic breast cancer oral abstract session at ASCO 2024.

Watch now

Highlights of the Day: Gynecologic cancer

Gynecologic Cancer Video

Highlights of the Day: Breast Cancer – local/regional/adjuvant

Breast Cancer Video

Neoadjuvant dual immunotherapy improves melanoma outcomes

04-06-2024 Melanoma News

» View more highlights on the ASCO 2024 congress hub page

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Image Credits

ASCO 2024 | Highlights of the Day: Breast cancer – metastatic/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Gynecologic Cancer/© 2024 American Society of Clinical Oncology, all rights reserved., ASCO 2024 | Highlights of the Day: Breast Cancer – local/regional/adjuvant/© 2024 American Society of Clinical Oncology, all rights reserved., Melanoma/© selvanegra / Getty Images / iStock, Antibody drug conjugated with cytotoxic payload/© Love Employee / Getty images / iStock

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2014

Quantitation of rare circulating tumor cells by folate receptor α ligand-targeted PCR in bladder transitional cell carcinoma and its potential diagnostic significance

CD 152 gene polymorphisms and risk of osteosarcoma in Chinese population

The roles of miR-200c in colon cancer and associated molecular mechanisms

Association of a genetic variant in microRNA-146a with risk of colorectal cancer: a population-based case-control study

NOV is upregulated and promotes migration and invasion in bladder cancer