title: 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.
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.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Lincai
authors.initials: L
authors.lastname: Ye
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
authors.affiliation: Medical Laboratory, Shanghai Pudong Gongli Hospital, No. 219 Miaopu Road, Pudong, Shanghai, 200135, People's Republic of China. yongbinchi66@aliyun.com.
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China. zhbheart@163.com.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; C561566:HOTAIR long untranslated RNA, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D062085:RNA, Long Noncoding
keywords: HIF-1α; HOTAIR; Hypoxia; Long noncoding RNA; Non-small cell lung cancer