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David A. Rowbotham

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    MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
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      MA24.07 - A Novel cis-Acting lncRNA Controls HMGA1 Expression in Lung Adenocarcinoma (ID 13979)

      11:10 - 11:15  |  Author(s): David A. Rowbotham

      • Abstract
      • Presentation
      • Slides


      High mobility group A1 (HMGA1) chromatin remodeling protein is enriched in several aggressive cancer types, including NSCLC, where mRNA and protein expression are markedly increased. Additionally, high HMGA1 expression has been associated with poor overall survival and chemotherapy resistance. While HMGA1 is deregulated in lung cancer, the mechanisms that mediate its expression are only beginning to emerge. Long non-coding RNAs (lncRNAs), are a class of transcripts have been implicated in the onset of cancer-associated phenotypes in tumourigenesis and metastasis. Recently, an emerging class of lncRNAs - cis-acting - has been shown to regulate the expression of neighbouring protein-coding genes, including oncogenes and tumour suppressor genes. Thus, lncRNAs may represent novel actionable therapeutic intervention points in known cancer driving pathways. Here we investigate the role of a cis-acting lncRNA, RP11.513I15.6, its deregulation in NSCLC, and its relationship with HMGA1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LncRNA transcriptomes were deduced from RNA-sequences of 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). Sequencing data obtained from The Cancer Genome Atlas were analyzed to validate these results. SiRNA-mediated knockdown of lncRNA candidates identified in these analyses were performed in a non-malignant lung epithelial cell line (BEAS-2B). Quantitative real-time PCR quantified the effects of lncRNA knockdown on the expression of neighbouring cancer-associated protein-coding genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Our analyses identified RP11.513I15.6, an undescribed lncRNA neighbouring HMGA1, to be significantly downregulated in adenocarcinoma (>2-fold downregulation in 81.5% of cases). This observation was confirmed in our validation cohort. HMGA1 expression was found to be anticorrelated with RP11.513I15.6, as tumours with downregulated RP11.513I15.6 displayed significant overexpression of HMGA1. This suggested that this lncRNA may be a key negative regulator of HMGA1. In vitro experiments demonstrated siRNA-mediated inhibition of RP11.513I15.6 in immortalized lung epithelial cells resulted in a significant increase in the expression of HMGA1 mRNA and protein. Taken together, 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 cancer phenotypes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have discovered a novel, 18-fold downregulated transcript that is anti-correlated with expression of HMGA1, a well established oncogene. In vitro studies support the hypothesis that this transcript, RP11.513I15.6, is a cis-acting lncRNA as siRNA-mediated inhibition led to upregulation of neighbouring HMGA1. Characterizing this oncogene regulatory mechanism will not only further our understanding of cancer biology, but could uncover a novel therapeutic intervention point.


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