Bleomycin-enhanced alternative splicing of fibroblast growth factor receptor 2 induces epithelial to mesenchymal transition in lung fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-β/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.

Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

“…Previous reports have shown that TGF-β drives EMT by down-regulating ESRP1 [30]. Thus, we investigated the effects of ESRP in BML-induced lung fibrosis and EMT.…”

“…In previous studies, we demonstrated that bleomycin induces EMT partly through activating TGF-β/Smad/ESRP1 signaling [17,30]. However, the mechanism of bFGF in bleomycin-induced EMT is not clear.…”

“…All mice were maintained specific pathogen-free (SPF) conditions with free access to water and laboratory rodent food. Lung fibrosis was induced by bleomycin in mice as described as previously [26]. Briefly, following anesthesia with 0.1% pentobarbital, mice received slow intratracheal injection with 6 mg/kg of bleomycin dissolved in saline, while control mice received saline only.…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…RNA‐binding proteins such as RNA‐binding Fox protein 2 (Rbfox2), epithelial splicing regulatory protein 1 (ESRP1), and ESRP2 control the splicing of many gene transcripts and splice nascent RNAs to functionally and structurally different miRNAs to regulate the process of EMT. For example, bleomycin inhibited ESRP1 expression, leading to the increased alternative splicing of FGFR2 to its mesenchymal isoform IIIc, which induced EMT in lung fibrosis . In addition, overexpressed ESRP1 contributed to EMT in ovarian cancer, inducing a cell‐specific variant of CD44 and a protein‐enabled homologue .…”

“…For example, bleomycin inhibited ESRP1 expression, leading to the increased alternative splicing of FGFR2 to its mesenchymal isoform IIIc, which induced EMT in lung fibrosis. 205 In addition, overexpressed ESRP1 contributed to EMT in ovarian cancer, inducing a cell-specific variant of CD44 and a protein-enabled homologue. 206 Moreover, Rbfox2 was upregulated during the EMT, and the depletion of Rbfox2 suppressed the expression of mesenchymal marker genes.…”