Abstract 312: Hypoxia induces EGFR inhibitor resistance in lung cancer cells via fibroblast growth factor receptor 1 (FGFR1) by promoting epithelial-mesenchymal transition (EMT)

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.

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Endothelial FGFR1 (Fibroblast Growth Factor Receptor 1) Deficiency Contributes Differential Fibrogenic Effects in Kidney and Heart of Diabetic Mice

Hypertension ◽

10.1161/hypertensionaha.120.15587 ◽

2020 ◽

Vol 76 (6) ◽

pp. 1935-1944 ◽

Cited By ~ 1

Author(s):

Jinpeng Li ◽

Haijie Liu ◽

Swayam Prakash Srivastava ◽

Qiongying Hu ◽

Rongfen Gao ◽

...

Keyword(s):

Diabetes Mellitus ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Epithelial To Mesenchymal Transition ◽

Fibroblast Growth Factor Receptor ◽

Growth Factor Receptor ◽

Fibroblast Growth ◽

Kidney Fibrosis ◽

Mesenchymal Transition ◽

Severe Fibrosis

Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. We have reported that N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP) restored levels of diabetes mellitus-suppressed FGFR1 (fibroblast growth factor receptor 1), the endothelial receptor essential for combating EndMT. However, the molecular regulation and biological/pathological significance of the AcSDKP-FGFR1 relationship has not been elucidated yet. Here, we demonstrated that endothelial FGFR1 deficiency led to AcSDKP-resistant EndMT and severe fibrosis associated with EndMT-stimulated fibrogenic programming in neighboring cells. Diabetes mellitus induced severe kidney fibrosis in endothelial FGFR1-deficient mice ( FGFR1 fl/fl ; VE-cadherin-Cre: FGFR1 EKO ) but not in control mice (FGFR1 fl/fl ); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1 EKO mice. Severe fibrosis was also induced in hearts of diabetic FGFR1 EKO mice; however, AcSDKP had no effect on heart fibrosis in FGFR1 EKO mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1 EKO mice. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelial-to-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-to-mesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP.

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