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Oesophagus
Original article
Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells
  1. Xue Yang1,2,3,4,
  2. Jee Hoon Song1,2,
  3. Yulan Cheng1,
  4. Wenjing Wu1,
  5. Tushar Bhagat5,
  6. Yiting Yu5,
  7. John M Abraham1,
  8. Sariat Ibrahim1,
  9. William Ravich1,
  10. Bani Chander Roland1,
  11. Mouen Khashab1,
  12. Vikesh K Singh1,
  13. Eun Ji Shin1,
  14. Xiao Yang3,4,
  15. Amit K Verma5,
  16. Stephen J Meltzer1,2,
  17. Yuriko Mori1
  1. 1Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3Model Organism Division, E-Institutes of Shanghai Universities, Shanghai Jiao-tong University School of Medicine, Shanghai, People's Republic of China
  4. 4State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, People's Republic of China
  5. 5Department of Medicine and Oncology, Albert Einstein College of Medicine, Bronx, New York, USA
  1. Correspondence to Dr Yuriko Mori, The Johns Hopkins University School of Medicine, 1503 E. Jefferson St., Room 101A, Baltimore, MD 21287, USA; ymori3{at}jhmi.edu; Dr Stephen J Meltzer, The Johns Hopkins University School of Medicine, 1503 E. Jefferson St., Room 112, Baltimore, MD 21287, USA; smeltzer{at}jhmi.edu

Abstract

Objectives Long non-coding RNAs (lncRNA) have been shown to play important roles in the development and progression of cancer. However, functional lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of oesophageal adenocarcinoma (EAC) and its progression.

Design lncRNAs that are abnormally upregulated in EACs were identified by RNA-sequencing analysis, followed by quantitative RT-PCR (qRTPCR) validation using tissues from 25 EAC patients. Cell biological assays in combination with small interfering RNA-mediated knockdown were performed in order to probe the functional relevance of these lncRNAs.

Results We discovered that a lncRNA, HNF1A-AS1, is markedly upregulated in human primary EACs relative to their corresponding normal oesophageal tissues (mean fold change 10.6, p<0.01). We further discovered that HNF1A-AS1 knockdown significantly inhibited cell proliferation and anchorage-independent growth, suppressed S-phase entry, and inhibited cell migration and invasion in multiple in vitro EAC models (p<0.05). A gene ontological analysis revealed that HNF1A-AS1 knockdown preferentially affected genes that are linked to assembly of chromatin and the nucleosome, a mechanism essential to cell cycle progression. The well known cancer-related lncRNA, H19, was the gene most markedly inhibited by HNF1A-AS1 knockdown. Consistent to this finding, there was a significant positive correlation between HNF1A-AS1 and H19 expression in primary EACs (p<0.01).

Conclusions We have discovered abnormal upregulation of a lncRNA, HNF1A-AS1, in human EAC. Our findings suggest that dysregulation of HNF1A-AS1 participates in oesophageal tumorigenesis, and that this participation may be mediated, at least in part, by modulation of chromatin and nucleosome assembly as well as by H19 induction.

  • Oesophageal Cancer
  • Cancer Genetics
  • Gene Expression

https://doi.org/10.1136/gutjnl-2013-305266

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