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D.D. Becker-Santos

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    MINI 34 - RNA and miRNA (ID 162)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI34.12 - Oncofetal miRNA Expression Inactivates Nuclear Factor I/B, a Critical Regulator of Lung Development and Lung Adenocarcinoma Pathogenesis (ID 3023)

      18:30 - 20:00  |  Author(s): D.D. Becker-Santos

      • Abstract
      • Slides

      Fetal development shares many biological similarities with tumourigenesis such as high rates of cell proliferation and vasculature restructuring. Particularly in the lung, a number of genes and pathways involved in the development of this organ play important roles in the malignant transformation of adult lung cells. Despite these biological similarities, there is a paucity of information regarding how specific molecular regulators involved in fetal lung development become oncogenes in lung cancer. This is the case for micro RNAs (miRNAs), which have a pivotal role in regulating gene expression during organ development and tumourigenesis. Therefore, a better understanding of the human fetal lung miRNA-transcriptome has the potential to reveal key players in lung cancer development and progression.

      131 pairs of non-small cell lung cancer (NSCLC) tumour and adjacent non-malignant lung tissues and 15 human fetal lung tissue samples were profiled by miRNA-sequencing. Mann–Whitney U tests were performed with Benjamini-Hochberg multiple testing corrections to identify miRNAs abundantly expressed in fetal and tumour tissues but scarce in non-malignant adult lung (i.e. oncofetal miRNAs). To investigate protein-coding genes controlled by the oncofetal miRNAs identified, miRDIP was applied followed by gene reporter luciferase assay experiments. The assessment of associations between patient survival and mRNA expression of selected genes targeted by the oncofetal miRNAs was evaluated in multiple NSCLC cohorts (>1,400 tumour cases). To validate the protein expression of the most prominent gene regulated by the oncofetal miRNAs identified, immunohistochemical (IHC) analysis was performed on a lung adenocarcinoma (LUAD) tissue microarray (TMA).

      We describe for the first time a comprehensive, unbiased characterization of miRNA expression in human fetal lung tissue by miRNA sequencing. Through comparison to a large cohort of NSCLC, we identified numerous miRNAs that recapitulate their fetal expression patterns in lung cancer. Strikingly, assessment of the genes potentially regulated by these oncofetal miRNAs led us to identify Nuclear Factor I/B (NFIB), a transcription factor essential for lung development, as being frequently targeted by oncofetal miRNAs. Concordantly, analysis of NFIB expression using RNA-sequencing data for multiple NSCLC cohorts revealed its frequent underexpression in tumours (>60%). Remarkably, low expression of NFIB was significantly associated with poorer survival in LUAD patients but not in squamous cell carcinoma patients, consistent with the functional role of NFIB in distal lung cell differentiation (i.e. cells that are the precursors of LUAD). Furthermore, an NFIB-related gene signature was identified in LUAD tumours and included several well-known lung differentiation markers (TTF-1, ABCA3, GPR116, SFTPB). Finally, the underexpression of NFIB protein was validated on a LUAD TMA, which also revealed that tumours presenting lower levels of this transcription factor are associated with higher grade, biologically more aggressive LUAD (invasive mucinous, micropapillary and solid subtypes).

      This work has revealed a prominent mechanism for the downregulation of a crucial gene for lung development, which we found to be associated with aggressive phenotypes of LUAD and consequently, poor patient survival. Elucidating the specific role of NFIB in lung cancer biology will likely lead to the identification of targetable tumour vulnerabilities.

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