BACKGROUND: Long non-coding RNAs (lncRNAs) have long been implicated in cancer-associated phenotypes. Recently, a class of lncRNAs, known as cis-acting, have been shown to regulate the expression of neighboring protein-coding genes and may represent undiscovered therapeutic action points. The chromatin architecture modification gene HMGA1 has recently been described to be aberrantly expressed in lung adenocarcinoma (LUAD). However, the mechanisms mediating the expression of HMGA1 in LUAD remain unknown. Here we investigate the deregulation of a putative cis-acting lncRNA in LUAD, and its effect on the oncogene HMGA1. METHODS: LncRNA expression was determined from RNA-sequencing data of tumor and matched non-malignant tissues from 36 LUAD patients. Transcripts with significantly deregulated expression were identified and validated in a secondary LUAD RNA-seq dataset (TCGA). SiRNA-mediated knockdown of a candidate cis-acting lncRNA was performed in BEAS-2B cells. Quantitative real-time PCR was used to observe the effects of lncRNA knockdown on the expression of HMGA1. RESULTS: We identified the lncRNA RP11.513I15.6, which we refer to as HMGA1-lnc, neighboring HMGA1 to be significantly downregulated in both LUAD cohorts. Conversely, we found HMGA1 significantly overexpressed in LUAD and anticorrelated with HMGA1-lnc. In vitro experiments demonstrated siRNA-mediated inhibition of HMGA1-lnc in immortalized non-malignant lung epithelial cells resulted in a significant increase in HMGA1 gene expression. CONCLUSION: Our results suggest that HMGA1-lnc is a novel cis-acting lncRNA that negatively regulates HMGA1 gene expression in lung cells. Further characterization of this regulatory mechanism may advance our understanding of the maintenance of lung cancer phenotypes and uncover a novel therapeutic intervention point for tumors driven by HMGA1.
BACKGROUND: Long non-coding RNAs (lncRNAs) have long been implicated in cancer-associated phenotypes. Recently, a class of lncRNAs, known as cis-acting, have been shown to regulate the expression of neighboring protein-coding genes and may represent undiscovered therapeutic action points. The chromatin architecture modification gene HMGA1 has recently been described to be aberrantly expressed in lung adenocarcinoma (LUAD). However, the mechanisms mediating the expression of HMGA1 in LUAD remain unknown. Here we investigate the deregulation of a putative cis-acting lncRNA in LUAD, and its effect on the oncogene HMGA1. METHODS: LncRNA expression was determined from RNA-sequencing data of tumor and matched non-malignant tissues from 36 LUAD patients. Transcripts with significantly deregulated expression were identified and validated in a secondary LUAD RNA-seq dataset (TCGA). SiRNA-mediated knockdown of a candidate cis-acting lncRNA was performed in BEAS-2B cells. Quantitative real-time PCR was used to observe the effects of lncRNA knockdown on the expression of HMGA1. RESULTS: We identified the lncRNA RP11.513I15.6, which we refer to as HMGA1-lnc, neighboring HMGA1 to be significantly downregulated in both LUAD cohorts. Conversely, we found HMGA1 significantly overexpressed in LUAD and anticorrelated with HMGA1-lnc. In vitro experiments demonstrated siRNA-mediated inhibition of HMGA1-lnc in immortalized non-malignant lung epithelial cells resulted in a significant increase in HMGA1 gene expression. CONCLUSION: Our results suggest that HMGA1-lnc is a novel cis-acting lncRNA that negatively regulates HMGA1 gene expression in lung cells. Further characterization of this regulatory mechanism may advance our understanding of the maintenance of lung cancer phenotypes and uncover a novel therapeutic intervention point for tumors driven by HMGA1.
Authors: Alexander Dobin; Carrie A Davis; Felix Schlesinger; Jorg Drenkow; Chris Zaleski; Sonali Jha; Philippe Batut; Mark Chaisson; Thomas R Gingeras Journal: Bioinformatics Date: 2012-10-25 Impact factor: 6.937
Authors: Kyoko L Yap; Side Li; Ana M Muñoz-Cabello; Selina Raguz; Lei Zeng; Shiraz Mujtaba; Jesús Gil; Martin J Walsh; Ming-Ming Zhou Journal: Mol Cell Date: 2010-06-11 Impact factor: 17.970
Authors: Thanasis Margaritis; Vincent Oreal; Nathalie Brabers; Laetitia Maestroni; Adeline Vitaliano-Prunier; Joris J Benschop; Sander van Hooff; Dik van Leenen; Catherine Dargemont; Vincent Géli; Frank C P Holstege Journal: PLoS Genet Date: 2012-09-20 Impact factor: 5.917
Authors: Paul Flicek; M Ridwan Amode; Daniel Barrell; Kathryn Beal; Konstantinos Billis; Simon Brent; Denise Carvalho-Silva; Peter Clapham; Guy Coates; Stephen Fitzgerald; Laurent Gil; Carlos García Girón; Leo Gordon; Thibaut Hourlier; Sarah Hunt; Nathan Johnson; Thomas Juettemann; Andreas K Kähäri; Stephen Keenan; Eugene Kulesha; Fergal J Martin; Thomas Maurel; William M McLaren; Daniel N Murphy; Rishi Nag; Bert Overduin; Miguel Pignatelli; Bethan Pritchard; Emily Pritchard; Harpreet S Riat; Magali Ruffier; Daniel Sheppard; Kieron Taylor; Anja Thormann; Stephen J Trevanion; Alessandro Vullo; Steven P Wilder; Mark Wilson; Amonida Zadissa; Bronwen L Aken; Ewan Birney; Fiona Cunningham; Jennifer Harrow; Javier Herrero; Tim J P Hubbard; Rhoda Kinsella; Matthieu Muffato; Anne Parker; Giulietta Spudich; Andy Yates; Daniel R Zerbino; Stephen M J Searle Journal: Nucleic Acids Res Date: 2013-12-06 Impact factor: 16.971