A novel cis-acting lncRNA controls HMGA1 expression and is deregulated in non-small cell lung cancer


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Greg Stewart1,Adam Sage1,Katey Enfield1,Erin Marshall1,Victor Martinez1,Wan Lam1
1BC Cancer Research Centre

Abstract

Background

High mobility group A1 (HMGA1) is aberrantly expressed in several aggressive cancer types, including non-small cell lung cancer (NSCLC), where high HMGA1 expression has been associated with poor survival and chemotherapy resistance. While HMGA1 is known to be deregulated in lung cancer, the mechanisms that mediate its expression remain unknown. Since their discovery, long non-coding RNAs (lncRNAs) have been increasingly implicated in cancer-associated phenotypes. Recently, some lncRNAs have been shown to regulate the expression of neighbouring protein-coding genes, including oncogenes and tumour suppressor genes. These lncRNAs, known as cis-acting, may represent undiscovered therapeutic action points in cancer driving pathways. Here we investigate the deregulation of a putative cis-acting lncRNA in NSCLC, and its relationship with the oncogene HMGA1.

Method

LncRNA expression was generated from RNA-sequencing data from 36 microdissected tumour and matched non-malignant tissues. Normalized sequence read counts were used to identify transcripts with significantly deregulated expression (Wilcoxon Signed-Rank Test, BH-p<0.05). Validation was performed in sequencing data obtained from The Cancer Genome Atlas (TCGA). SiRNA-mediated knockdown of lncRNA candidates was performed in a non-malignant epithelial lung cell line (BEAS-2B). Quantitative real-time PCR was used to observe the effects of lncRNA knockdown on the expression of neighbouring protein-coding genes.

Results

Our analyses identified RP11.513I15.6, an undescribed lncRNA neighbouring HMGA1, to be significantly downregulated in 2 cohorts of LUAD samples. HMGA1 expression was found to be anticorrelated with RP11.513I15.6, as tumours with downregulated RP11.513I15.6 displayed significant overexpression of HMGA1. In vitro experiments demonstrated siRNA-mediated inhibition of RP11.513I15.6 in immortalized lung epithelial cells resulted in a significant increase in HMGA1 expression.

Conclusion

Our results suggest that RP11.513I15.6 is a novel cis-acting lncRNA that negatively regulates HMGA1, and may contribute mechanistically to the maintenance of lung cancer phenotypes. Further characterization of this oncogenic regulatory mechanism may uncover a novel therapeutic intervention point for tumours driven by HMGA1.