RESUMO
The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy.
Assuntos
Homeostase , Proteína 2 Reguladora do Ferro , Ferro , Neoplasias da Próstata , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Ferro/metabolismo , Proteína 2 Reguladora do Ferro/metabolismo , Proteína 2 Reguladora do Ferro/genética , Linhagem Celular Tumoral , Animais , Proteólise , Camundongos , Regulação Neoplásica da Expressão Gênica , Receptores da Transferrina/metabolismo , Receptores da Transferrina/genética , Antígenos CDRESUMO
Fibroblast growth factor 9 (FGF9) is a member of the fibroblast growth factor family, which is widely expressed in the central nervous system (CNS). It has been reported that deletion of FGF9 leads to defects in cerebellum development, including Purkinje cell defect. However, it is not clear how FGF9 regulating cerebellar development remains to be determined. Our results showed that in addition to disrupt Bergmann fiber scaffold formation and granule neuron migration, deletion of neuronal FGF9 led to ataxia defects. It affected development and function of Purkinje cells, and also changed the action potential threshold and excitation frequency. Mechanistically, depletion of FGF9 significantly changed neurotransmitter contents in Purkinje cells and led to preferential increase in inflammation, even downregulation in ERK signaling. Together, the data demonstrate that neuronal FGF9 is required for the development and function of Purkinje cells in the cerebellum. Insufficient FGF9 during cerebellum development will cause ataxia defects.
RESUMO
Sustainable development of rural has become an essential global plan. Habitat sustainability assessment of rural is a critical management tool to grasp the development status of rural in real-time and enable dynamic adjustment of policies. This paper combines the 2030 Sustainable Development Goals (SDGs) with the entropy weight method, TOPSIS, and grey correlation analysis to construct a multi-criteria decision-making (MCDM) evaluation model, which is finally used to assess the sustainability of the rural human settlement environment. Finally, this paper uses the rural of 11 prefecture-level cities in Zhejiang Province in 2021 as a case study for rural human settlement environment sustainability evaluation. The results show that the overall rural human settlement environment sustainability level in Zhejiang Province is better than in most regions in China. Hangzhou has the best rural human settlement environment sustainability, and Zhoushan has the worst. In addition, the production environment factor is the critical factor that constrains sustainability. The study results provide references and guidance to policymakers for sustainable development initiatives.