Tumor Biology

, Volume 36, Issue 12, pp 9179–9188 | Cite as

Long noncoding RNA HOTAIR, a hypoxia-inducible factor-1α activated driver of malignancy, enhances hypoxic cancer cell proliferation, migration, and invasion in non-small cell lung cancer

Research Article

Abstract

Despite the fact that great advances have been made in the management of non-small cell lung cancer (NSCLC), the prognosis of advanced NSCLC remains very poor. HOX transcript antisense intergenic RNA (HOTAIR) has been identified as an oncogenic long noncoding RNA (lncRNA) that is involved in the progression of a variety of carcinomas and acts as a negative prognostic biomarker. Yet, little is known about the effect of HOTAIR in the hypoxic microenvironment of NSCLC. The expression and promoter activity of HOTAIR were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay. The function of the hypoxia-inducible factor-1α (HIF-1α) binding site to hypoxia-responsive elements (HREs) in the HOTAIR promoter region was tested by luciferase reporter assay with nucleotide substitutions. The binding of HIF-1α to the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay (CHIP) and electrophoretic mobility shift assay (EMSA). The effect of HIF-1α suppression by small interference RNA or YC-1 on HOTAIR expression was also determined. In the present study, we demonstrated that HOTAIR was upregulated by hypoxia in NSCLC cells. HOTAIR is a direct target of HIF-1α through interaction with putative HREs in the upstream region of HOTAIR in NSCLC cells. Furthermore, HIF-1α knockdown or inhibition could prevent HOTAIR upregulation under hypoxic conditions. Under hypoxic conditions, HOTAIR enhanced cancer cell proliferation, migration, and invasion. These data suggested that suppression of HOTAIR upon hypoxia of NSCLC could be a novel therapeutic strategy.

Keywords

Non-small cell lung cancer Long noncoding RNA HOTAIR Hypoxia HIF-1α 

Notes

Acknowledgments

This work was supported by Shanghai Municipal Natural Science Foundation (No. 13ZR1437100) and the Key Discipline Construction Project of Pudong Health Bureau of Shanghai (No. PWZx2014-03). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

Conflicts of interest

None

References

  1. 1.
    Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11:393–410.CrossRefPubMedGoogle Scholar
  2. 2.
    Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107(6):1053–62.CrossRefPubMedGoogle Scholar
  3. 3.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12(2):149–62.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yang F, Zhang H, Mei Y, Wu M. Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect. Mol Cell. 2014;53(1):88–100.CrossRefPubMedGoogle Scholar
  5. 5.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Samanta D, Gilkes DM, Chaturvedi P, Xiang L, Semenza GL. Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proc Natl Acad Sci U S A. 2014;111(50):E5429–38.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Semenza GL. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene. 2013;32(35):4057–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Smith RA, Manassaram-Baptiste D, Brooks D, Cokkinides V, Doroshenk M, Saslow D, et al. Cancer screening in the United States, 2014: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2014;64(1):30–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L, et al. EUROCARE-4 working group: recent cancer survival in Europe: a 2000–02 period analysis of EUROCARE-4 data. Lancet Oncol. 2007;8(9):784–96.CrossRefPubMedGoogle Scholar
  10. 10.
    Bryant JL, Meredith SL, Williams KJ, White A. Targeting hypoxia in the treatment of small cell lung cancer. Lung Cancer. 2014;86(2):126–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Martinengo C, Poggio T, Menotti M, Scalzo MS, Mastini C, Ambrogio C, et al. ALK-dependent control of hypoxia-inducible factors mediates tumor growth and metastasis. Cancer Res. 2014;74(21):6094–106.CrossRefPubMedGoogle Scholar
  12. 12.
    Jackson AL, Zhou B, Kim WY. HIF, hypoxia and the role of angiogenesis in non-small cell lung cancer. Expert Opin Ther Targets. 2010;14(10):1047–57.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhang D, Shi Z, Li M, Mi J. Hypoxia-induced miR-424 decreases tumor sensitivity to chemotherapy by inhibiting apoptosis. Cell Death Dis. 2014;5, e1301.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lan J, Xue Y, Chen H, Zhao S, Wu Z, Fang J, et al. Hypoxia-induced miR-497 decreases glioma cell sensitivity to TMZ by inhibiting apoptosis. FEBS Lett. 2014;588(18):3333–9.CrossRefPubMedGoogle Scholar
  15. 15.
    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
  16. 16.
    Ma MZ, Chu BF, Zhang Y, Weng MZ, Qin YY, Gong W, et al. Long non-coding RNA CCAT1 promotes gallbladder cancer development via negative modulation of miRNA-218-5p. Cell Death Dis. 2015;6, e1583.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25(5):666–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Ma MZ, Li CX, Zhang Y, Weng MZ, Zhang MD, Qin YY, et al. Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol Cancer. 2014;13:156.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liu XH, Liu ZL, Sun M, Liu J, Wang ZX, De W. The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer. BMC Cancer. 2013;13:464.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bhan A, Hussain I, Ansari KI, Kasiri S, Bashyal A, Mandal SS. Antisense transcript long noncoding RNA (lncRNA) HOTAIR is transcriptionally induced by estradiol. J Mol Biol. 2013;425(19):3707–22.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–34.CrossRefPubMedGoogle Scholar
  24. 24.
    Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wong WJ, Qiu B, Nakazawa MS, Qing G, Simon MC. MYC degradation under low O2 tension promotes survival by evading hypoxia-induced cell death. Mol Cell Biol. 2013;33(17):3494–504.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hwang IY, Roe JS, Seol JH, Kim HR, Cho EJ, Youn HD. pVHL-mediated transcriptional repression of c-Myc by recruitment of histone deacetylases. Mol Cell. 2012;33(2):195–201.CrossRefGoogle Scholar
  27. 27.
    Doe MR, Ascano JM, Kaur M, Cole MD. Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res. 2012;72(4):949–57.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Thoracic and Cardiovascular Surgery, Shanghai Children’s Medical CenterShanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Institute of Pediatric Translational Medicine, Shanghai Children’s Medical CenterShanghai Jiaotong University School of MedicineShanghaiChina
  3. 3.Medical LaboratoryShanghai Pudong Gongli HospitalShanghaiPeople’s Republic of China

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