HOX transcript antisense intergenic RNA represses E-cadherin expression by binding to EZH2 in gastric cancer

World J Gastroenterol. 2017 Sep 7;23(33):6100-6110. doi: 10.3748/wjg.v23.i33.6100.


Aim: To clarify the mechanisms of HOX transcript antisense intergenic RNA (HOTAIR) in gastric cancer (GC) migration and invasion.

Methods: Quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression level of HOTAIR in GC tissues. The correlation of its expression with clinicopathological features was analyzed. Area under receiver operating characteristic curve (AUCROC) was constructed to evaluate the diagnostic value of HOTAIR. Wound-healing assay and Transwell assay were performed to detect the biological effects of HOTAIR in GC cells. qPCR, western blot and immunohistochemistry were used to evaluate the mRNA and protein expression of E-cadherin. RNA-binding protein immunoprecipitation was used for the analysis of EZH2 interactions with HOTAIR. Chromatin immunoprecipitation assay was performed to investigate direct interactions between EZH2 and E-cadherin.

Results: The expression of HOTAIR was up-regulated in GC tumorous tissues compared with the para-tumorous tissues (P < 0.001). Its over-expression was correlated with tumor-node-metastasis (TNM) stage (P = 0.024), tumor invasion (P = 0.018), lymph node metastasis (P = 0.023), and poor prognosis (P < 0.001). Multivariate Cox regression analysis confirmed expression of HOTAIR as an independent predictor of overall survival (P = 0.033), together with TNM stage (P = 0.002) and lymph node metastasis (P = 0.002). The AUCROC was up to 0.709 (95%CI: 0.623-0.785, P < 0.001). Knockdown of HOTAIR by siRNA in GC cells suppressed the migration and invasion of GC cells. Significantly negative correlation between HOTAIR and E-cadherin was found in GC tissues and cell lines, and HOTAIR contributed to the regulation of E-cadherin through binding to EZH2 with the E-cadherin promoter.

Conclusion: HOTAIR may play a pivotal role in tumor cell migration and invasion. It can be used as a potential diagnostic and prognostic biomarker for GC.

Keywords: E-cadherin; Gastric cancer; HOX transcript antisense intergenic RNA; Long noncoding RNA; Migration and invasion.

MeSH terms

  • Antigens, CD
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Chromatin Immunoprecipitation
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Neoplasm Invasiveness / genetics
  • Neoplasm Staging
  • Prognosis
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Up-Regulation


  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • Cadherins
  • HOTAIR long untranslated RNA, human
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Small Interfering
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein