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Tumor Biology

, Volume 37, Issue 2, pp 1379–1385 | Cite as

Influence of the interaction between long noncoding RNAs and hypoxia on tumorigenesis

  • Jun Dong
  • Jiangbing Xu
  • Xiang Wang
  • Bilian Jin
Review

Abstract

The interaction between cancer and its microenvironment is crucial for survival and development of cancerous cells. Tumor microenvironment is usually under hypoxia, which promotes tumor aggressiveness like growth, angiogenesis, and metastasis. How cancer cells respond to hypoxia and the resultant impact on tumorigenesis are not yet fully explored. Long noncoding RNAs (lncRNAs) have been attracting more and more attention since their functions in regulating gene expression at chromatic, transcriptional, and posttranscriptional levels were found. lncRNAs are dysregulated in cancer and act as oncogenes or tumor suppressors. Moreover, emerging evidence has been provided that the expression of lncRNAs changes with the stimulus of hypoxia and they in turn produce a significant influence on the hypoxia-inducible factor (HIF), the most common transcription regulator in response to hypoxia. In this review, we discuss the recent findings of hypoxia-responsive lncRNAs and summarize their interaction with hypoxia to further understand their roles in cancer growth, metabolism, angiogenesis, and metastasis and their potential for cancer diagnosis and treatment.

Keywords

Hypoxia Long noncoding RNA Hypoxia-inducible factor Interaction Tumorigenesis Biomarker 

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (nos. 81372713, 81402048).

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Lodish H, Berk A, Zipursky SL et al. (2000) Tumor cells and the onset of cancer; Molecular cell biology, ed4. New York, W. H. FreemanGoogle Scholar
  2. 2.
    Wels J, Kaplan RN, Rafii S, Lyden D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 2008;22:559–74.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38–47.CrossRefPubMedGoogle Scholar
  4. 4.
    Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. Cancer discovery. 2011;1:391–407.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Autuoro JM, Pirnie SP, Carmichael GG. Long noncoding RNAs in imprinting and x chromosome inactivation. Biomolecules. 2014;4:76–100.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kornienko AE, Guenzl PM, Barlow DP, Pauler FM. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 2013;11:59.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yoon JH, Abdelmohsen K, Gorospe M. Posttranscriptional gene regulation by long noncoding RNA. J Mol Biol. 2013;425:3723–30.CrossRefPubMedGoogle Scholar
  9. 9.
    Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett. 2013;339:159–66.CrossRefPubMedGoogle Scholar
  10. 10.
    Xue M, Li X, Li Z, Chen W. Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1alpha-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion. Oncogene. 2014;35:6901–12.Google Scholar
  11. 11.
    Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E, et al. Oncofetal h19 RNA promotes tumor metastasis. Biochim Biophys Acta. 1843;2014:1414–26.Google Scholar
  12. 12.
    Fish JE, Matouk CC, Yeboah E, Bevan SC, Khan M, Patil K, et al. Hypoxia-inducible expression of a natural cis-antisense transcript inhibits endothelial nitric-oxide synthase. J Biol Chem. 2007;282:15652–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Shen XH, Qi P, Du X. Long non-coding RNAs in cancer invasion and metastasis. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc, 2015;28:4–13.CrossRefGoogle Scholar
  14. 14.
    Gomez-Maldonado L, Tiana M, Roche O, Prado-Cabrero A, Jensen L, Fernandez-Barral A, et al. EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination. Oncogene. 2014;34(20):2609–200.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhou C, Ye L, Jiang C, Bai J, Chi Y, Zhang H: Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1alpha activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine 2015 (in press)Google Scholar
  16. 16.
    Choudhry H, Schodel J, Oikonomopoulos S, Camps C, Grampp S, Harris AL, et al. Extensive regulation of the non-coding transcriptome by hypoxia: role of HIF in releasing paused RNAPOL2. EMBO Rep. 2014;15:70–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Choudhry H, Albukhari A, Morotti M, Hider S, Moralli D, Smythies J, Schodel J, Green CM, Camps C, Buffa F, Ratcliffe P, Ragoussis J, Harris AL, Mole DR: Tumor hypoxia induces nuclear paraspeckle formation through HIF-2alpha dependent transcriptional activation of NEAT1 leading to cancer cell survival. Oncogene. 2015;34:4482–90.Google Scholar
  18. 18.
    Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell. 2011;43:811–22.CrossRefPubMedGoogle Scholar
  19. 19.
    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;49:1083–96.CrossRefPubMedGoogle Scholar
  20. 20.
    McCarty G, Loeb DM. Hypoxia-sensitive epigenetic regulation of an antisense-oriented lncRNA controls wt1 expression in myeloid leukemia cells. PLoS One. 2015;10:e0119837.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    He Y, Vogelstein B, Velculescu VE, Papadopoulos N, Kinzler KW. The antisense transcriptomes of human cells. Science. 2008;322:1855–7.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Villegas VE, Zaphiropoulos PG. Neighboring gene regulation by antisense long non-coding RNAs. Int J Mol Sci. 2015;16:3251–66.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bertozzi D, Iurlaro R, Sordet O, Marinello J, Zaffaroni N, Capranico G. Characterization of novel antisense HIF-1alpha transcripts in human cancers. Cell Cycle. 2011;10:3189–97. Georgetown, Tex.Google Scholar
  25. 25.
    Wang Y, Yao J, Meng H, Yu Z, Wang Z, Yuan X, et al. A novel long non-coding RNA, hypoxia-inducible factor-2alpha promoter upstream transcript, functions as an inhibitor of osteosarcoma stem cells in vitro. Mol Med Rep. 2015;11:2534–40.PubMedGoogle Scholar
  26. 26.
    Sun YW, Chen YF, Li J, Huo YM, Liu DJ, Hua R, et al. A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1alpha in pancreatic ductal adenocarcinoma. Br J Cancer. 2014;111:2131–41.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, Pearson M, et al. Os-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Mol Cell. 2005;17:503–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Wong BW, Kuchnio A, Bruning U, Carmeliet P. Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes. Trends Biochem Sci. 2013;38:3–11.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhu Z, Gao X, He Y, Zhao H, Yu Q, Jiang D, et al. An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk. Cancer Res. 2012;72:6163–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Yang F, Zhang H, Mei Y, Wu M. Reciprocal regulation of HIF-1alpha and lincRNA-p21 modulates the Warburg effect. Mol Cell. 2014;53:88–100.CrossRefPubMedGoogle Scholar
  31. 31.
    Ma MZ, Kong X, Weng MZ, Zhang MD, Qin YY, Gong W, et al. Long non-coding RNA-LET is a positive prognostic factor and exhibits tumor-suppressive activity in gallbladder cancer. Mol Carcinog. 2014;54(11):1397–406.CrossRefPubMedGoogle Scholar
  32. 32.
    Takahashi K, Yan IK, Haga H, Patel T. Modulation of hypoxia-signaling pathways by extracellular linc-ror. J Cell Sci. 2014;127:1585–94.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Xu Q, Liu LZ, Qian X, Chen Q, Jiang Y, Li D, et al. Mir-145 directly targets p70s6k1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res. 2012;40:761–74.CrossRefPubMedGoogle Scholar
  34. 34.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.CrossRefPubMedGoogle Scholar
  35. 35.
    Ferdin J, Nishida N, Wu X, Nicoloso MS, Shah MY, Devlin C, et al. HINCUTS in cancer: hypoxia-induced noncoding ultraconserved transcripts. Cell Death Differ. 2013;20:1675–87.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Nolte D, Muller U. Human o-GlcNAc transferase (OGT): genomic structure, analysis of splice variants, fine mapping in xq13.1. Mammalian genome: official journal of the International Mammalian Genome Society. 2002;13:62–4.CrossRefGoogle Scholar
  37. 37.
    Kreppel LK, Blomberg MA, Hart GW. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique o-GlcNAc transferase with multiple tetratricopeptide repeats. J Biol Chem. 1997;272:9308–15.CrossRefPubMedGoogle Scholar
  38. 38.
    Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21:485–95.CrossRefPubMedGoogle Scholar
  39. 39.
    Goldar S, Khaniani MS, Derakhshan SM, Baradaran B. Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pacific journal of cancer prevention: APJCP. 2015;16:2129–44.CrossRefPubMedGoogle Scholar
  40. 40.
    Soussi T. The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci. 2000;910:121–37. discussion 137–129.Google Scholar
  41. 41.
    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:e845.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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. 1803;2010:443–51.Google Scholar
  43. 43.
    Rossi MN, Antonangeli F. LncRNAs: new players in apoptosis control. International journal of cell biology. 2014;2014:473857.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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 resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2007;10:13–29.CrossRefGoogle Scholar
  45. 45.
    Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.CrossRefPubMedGoogle Scholar
  46. 46.
    Bartrons R, Caro J. Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr. 2007;39:223–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Zeng W, Liu P, Pan W, Singh SR, Wei Y. Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett. 2015;356:263–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Bikfalvi A. Angiogenesis and invasion in cancer. Handb Clin Neurol. 2012;104:35–43.CrossRefPubMedGoogle Scholar
  49. 49.
    Raghunand N, Gatenby RA, Gillies RJ. Microenvironmental and cellular consequences of altered blood flow in tumours. Br J Radiol. 2003;76 Spec No 1:S11–22.CrossRefPubMedGoogle Scholar
  50. 50.
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.CrossRefPubMedGoogle Scholar
  51. 51.
    Chen L, Endler A, Shibasaki F. Hypoxia and angiogenesis: regulation of hypoxia-inducible factors via novel binding factors. Exp Mol Med. 2009;41:849–57.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mizukami Y, Kohgo Y, Chung DC. Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clinical cancer research: an official journal of the American Association for Cancer Research. 2007;13:5670–4.CrossRefGoogle Scholar
  53. 53.
    Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–41.CrossRefPubMedGoogle Scholar
  54. 54.
    Michalik KM, You X, Manavski Y, Doddaballapur A, Zornig M, Braun T, et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res. 2014;114:1389–97.CrossRefPubMedGoogle Scholar
  55. 55.
    Weigelt B, Peterse JL, Veer LJ v ’t. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.CrossRefPubMedGoogle Scholar
  56. 56.
    Wang Y, Liu X, Zhang H, Sun L, Zhou Y, Jin H, et al. Hypoxia-inducible lncRNA-ak058003 promotes gastric cancer metastasis by targeting gamma-synuclein. Neoplasia. 2014;16:1094–106.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Van Roosbroeck K, Pollet J, Calin GA. MiRNAs and long noncoding RNAs as biomarkers in human diseases. Expert Rev Mol Diagn. 2013;13:183–204.CrossRefPubMedGoogle Scholar
  58. 58.
    Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, et al. Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell. 2015;28:529–40.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist. 2008;13 Suppl 3:21–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang Q, Su M, Lu G, Wang J. The complexity of bladder cancer: long noncoding RNAs are on the stage. Mol Cancer. 2013;12:101.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zheng Q, Wu F, Dai WY, Zheng DC, Zheng C, Ye H, Zhou B, Chen JJ, Chen P: Aberrant expression of UCA1 in gastric cancer and its clinical significance. Clinical & translational oncology: official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. Clin Transl Oncol. 2015;17:640–6.Google Scholar
  62. 62.
    Hughes JM, Legnini I, Salvatori B, Masciarelli S, Marchioni M, Fazi F, et al. C/EBPalpha-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia. Oncotarget. 2015;6(21):18534–44.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Zhou X, Yin C, Dang Y, Ye F, Zhang G. Identification of the long non-coding RNA h19 in plasma as a novel biomarker for diagnosis of gastric cancer. Sci Rep. 2015;5:11516.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Li CH, Chen Y. Targeting long non-coding RNAs in cancers: progress and prospects. Int J Biochem Cell Biol. 2013;45:1895–910.CrossRefPubMedGoogle Scholar
  65. 65.
    Qi P, Du X. The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc. 2013;26:155–65.CrossRefGoogle Scholar
  66. 66.
    Smaldone MC, Davies BJ. Bc-819, a plasmid comprising the h19 gene regulatory sequences and diphtheria toxin a, for the potential targeted therapy of cancers. Curr Opin Mol Ther. 2010;12:607–16.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Institute of Cancer Stem CellDalian Medical UniversityDalianChina

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