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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

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Tumor Biology

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.

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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.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Chunxia Zhou & Haibo Zhang

  2. Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Lincai Ye, Chuan Jiang & Jie Bai

  3. Medical Laboratory, Shanghai Pudong Gongli Hospital, No. 219 Miaopu Road, Pudong, Shanghai, 200135, People’s Republic of China

    Yongbin Chi

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  1. Chunxia Zhou
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  2. Lincai Ye
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  5. Yongbin Chi
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Correspondence to Yongbin Chi or Haibo Zhang.

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Zhou, C., Ye, L., Jiang, C. et al. 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. Tumor Biol. 36, 9179–9188 (2015). https://doi.org/10.1007/s13277-015-3453-8

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  • DOI: https://doi.org/10.1007/s13277-015-3453-8

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