Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma

作者：Becker Santos Daiana D^*; Thu Kelsie L; English John C; Pikor Larissa A; Martinez Victor D; Zhang May; Vucic Emily A; Luk Margaret T Y; Carraro Anita; Korbelik Jagoda; Piga Daniela; Lhomme Nicolas M; Tsay Mike J; Yee John; MacAulay Calum E; Lam Stephen; Lockwood William W; Robinson Wendy P; Jurisica Igor; Lam Wan L

来源：Journal of Pathology, 2016, 240(2): 161-172.

DOI：10.1002/path.4765

• miRNAs
• miRNA sequencing
• lung adenocarcinoma (LUAD)
• lineage transcription factors
• lung development

Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these 'oncofetal' miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in similar to 40-70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients.

• 出版日期2016-10