AUTHOR=Stewart Greg L. , Sage Adam P. , Enfield Katey S. S. , Marshall Erin A. , Cohn David E. , Lam Wan L. 

TITLE=Deregulation of a Cis-Acting lncRNA in Non-small Cell Lung Cancer May Control HMGA1 Expression

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.615378

DOI=10.3389/fgene.2020.615378

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>Long non-coding RNAs (lncRNAs) have long been implicated in cancer-associated phenotypes. Recently, a class of lncRNAs, known as <italic>cis</italic>-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 <italic>HMGA1</italic> has recently been described to be aberrantly expressed in lung adenocarcinoma (LUAD). However, the mechanisms mediating the expression of <italic>HMGA1</italic> in LUAD remain unknown. Here we investigate the deregulation of a putative <italic>cis</italic>-acting lncRNA in LUAD, and its effect on the oncogene <italic>HMGA1</italic>.</p></sec><sec><title>Methods</title><p>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 <italic>cis</italic>-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.</p></sec><sec><title>Results</title><p>We identified the lncRNA RP11.513I15.6, which we refer to as HMGA1-<italic>lnc</italic>, neighboring <italic>HMGA1</italic> to be significantly downregulated in both LUAD cohorts. Conversely, we found <italic>HMGA1</italic> significantly overexpressed in LUAD and anticorrelated with HMGA1-<italic>lnc</italic>. <italic>In vitro</italic> experiments demonstrated siRNA-mediated inhibition of HMGA1-<italic>lnc</italic> in immortalized non-malignant lung epithelial cells resulted in a significant increase in <italic>HMGA1</italic> gene expression.</p></sec><sec><title>Conclusion</title><p>Our results suggest that HMGA1-<italic>lnc</italic> is a novel <italic>cis</italic>-acting lncRNA that negatively regulates <italic>HMGA1</italic> 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 <italic>HMGA1</italic>.</p></sec>