title: MiR-365 regulates lung cancer and developmental gene thyroid transcription factor 1.
abstract: Thyroid transcription factor 1 (TTF-1 or NKX2-1) is an essential fetal lung developmental factor, which can be recurrently activated by gene amplification in adult lung cancer. We have discovered the first microRNA (i.e., miR-365) that directly regulates TTF-1 by interacting with its 3'-untranslated region. By gene expression profiling, we identified other putative targets of miR-365 and miR-365*. In line with the microRNA/target relationship, the expression patterns of miR-365 and TTF-1 were in an inverse relationship in human lung cancer. Exploration of human lung cancer genomics data uncovered that TTF-1 gene amplification was significantly associated with DNA copy number loss at one of the two genomic loci encoding the precursor RNA of mature miR-365 (i.e., mir-365-1). This implies the existence of genetic selection pressure to lose the repressive miR-365 that would otherwise suppress amplified TTF-1. We detected a signaling loop between transforming growth factor beta (TGFb) and miR-365 and this loop reinforced suppression of TTF-1 via miR-365. Mir-365 also targeted an epithelial mesenchymal transition (EMT)-promoting gene HMGA2. In summary, these data connect the lung transcriptional program to the microRNA network.
authors.affiliation: Department of Pathology, Pennsylvania State College of Medicine, Hershey, PA, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Qi
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Rice
authors.forename: Anna C
authors.initials: AC
authors.lastname: Salzberg
authors.forename: E Aaron
authors.initials: EA
authors.lastname: Runkle
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Dani S
authors.initials: DS
authors.lastname: Zander
authors.forename: David
authors.initials: D
authors.lastname: Mu
mesh_terms: D020413:3' Untranslated Regions; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D025743:HMGA2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D025743:HMGA2 Protein; C546819:MIRN365 microRNA, human; D035683:MicroRNAs; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta