Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

Abstract

Better understanding alveolarization mechanisms could help improve prevention and treatment of diseases characterized by reduced alveolar number. Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18, the expression of which peaks coincidentally with alveolar septation, is likely to be involved. Herein, a mouse model with inducible, lung-targeted FGF18 transgene was used to advance the onset of FGF18 expression peak, and genome-wide expression changes were determined by comparison with littermate controls. Quantitative RT-PCR was used to confirm expression changes of selected up- and downregulated genes and to determine their expression profiles in the course of lung postnatal development. This allowed identifying so-far unknown target genes of the factor, among which a number are known to be involved in alveolarization. The major target was adrenomedullin, a promoter of lung angiogenesis and alveolar development, whose transcript was increased 6.9-fold. Other genes involved in angiogenesis presented marked expression increases, including Wnt2 and cullin2. Although it appeared to favor cell migration notably through enhanced expression of Snai1/2, FGF18 also induced various changes consistent with prevention of epithelial-mesenchymal transition. Together with antifibrotic effects driven by induction of E prostanoid receptor 2 and repression of numerous myofibroblast markers, this could prevent alveolar septation-driving mechanisms from becoming excessive and deleterious. Last, FGF18 up- or downregulated genes of extracellular matrix components and epithelial cell markers previously shown to be up- or downregulated during alveolarization. These findings therefore argue for an involvement of FGF18 in the control of various developmental events during the alveolar stage.

FGF18 as a prognostic and therapeutic biomarker in ovarian cancer

“…Despite minimal effects on cellular proliferation (Supplemental Figure 5), ectopic FGF18 overexpression significantly increased cellular migration and invasion of both A224 and OVCA429 cells ( Figure 3C). FGF18 is a member of the FGF family of ligands that have profound effects on blood vessel formation in physiological development (9)(10)(11). To test the potential role of FGF18 in angiogenesis, we investigated the effect of FGF18 on HUVEC motility and tube formation.…”

“…Targeted disruption of FGF18 in mice is lethal beyond birth due to impaired skeleton development and alveologenesis, but Fgf1/Fgf2 double-knockout mice are fertile without any gross phenotypic defects (7,8), suggesting unique roles of FGF18 in both embryonic and postnatal development. Acting as a mitogenic, chemotactic, and angiogenic factor, FGF18 is required for the development of bone, cartridge, hair, cardiovasculature, and alveolus (8)(9)(10)(11). Nevertheless, the function of FGF18 has never been studied in the context of serous ovarian cancer.…”

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

“…Recent data revealed that the blockade of DIAPH1-tubulin interaction might be a promising approach to inhibit one of the earliest steps in the metastatic cascade of colon cancer [43]. FGF18 is a pleiotropic growth factor involved in skeletal growth and development [44, 45]. Deregulated FGF signaling may affect some oncogenic mechanisms and properties in various tumor types [46].…”

FGF18 as a potential biomarker in serous and mucinous ovarian tumors

“…Acting as a mitogenic, chemotactic, and angiogenic factor, FGF18 is required for the development of bone, cartilage, hair, cardiovasculature, and alveoli [14,[17][18][19]. Pathologically, two studies assigned a role for FGF18 in colorectal [20] and ovarian carcinogenesis [12].…”