Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links Loss to the Pathogenesis of Pleuropulmonary Blastoma

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Pleuropulmonary Blastoma (PPB) is a pediatric disease that presents with multifocal cystic lung lesions. Familial mutations in DICER1, an essential gene for microRNA synthesis, predisposes to PPB and other related diseases. Loss or mutation of the second copy of DICER1 in developing airway epithelium is thought to initiate cyst formation and increase growth of the underlying mesenchyme. In later stages, additional genetic events in PPB mesenchyme (mutations in the DICER1 RNase IIIb domain or in TP53) can lead to the formation of high-grade sarcomas. We hypothesized that loss of DICER1 function in lung epithelium leads to persistent overgrowth of mesenchyme (and subsequent risk for malignancy), implicating an indirect tumor initiation mechanism. In this study, we show histological and molecular similarity in Type I PPB and mice lacking epithelial Dicer1 or overexpressing epithelial Fibroblast Growth Factor 9 (Fgf9), demonstrate increased FGF9 expression in Type I PPB and in Dicer1-deficient mouse lung epithelium, and show that Fgf9 mediates at least some of the pathology resulting from Dicer1 inactivation in lung epithelium. Finally, we show that specific lung epithelial microRNAs regulate Fgf9. These studies identify FGF9 as a target of DICER1 in lung epithelium that functions as an initiating factor for PPB.

Vyšlo v časopise: Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links Loss to the Pathogenesis of Pleuropulmonary Blastoma. PLoS Genet 11(5): e32767. doi:10.1371/journal.pgen.1005242
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005242

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