查看更多>>摘要：Cartilage development is controlled by the highly synergistic proliferation and dif-ferentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced(I RE1 α/XBP1 s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage develop-ment.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation.
查看更多>>摘要：Glioblastoma(GBM)is a malignant brain tumor that grows quickly,spreads widely,and is resistant to treatment.Fibroblast growth factor receptor(FGFR)1 is a receptor tyrosine kinase that regulates cellular processes,including proliferation,survival,migration,and dif-ferentiation.FGFR1 was predominantly expressed in GBM tissues,and FGFR1 expression was negatively correlated with overall survival.We rationally designed a novel small molecule CYY292,which exhibited a strong affinity for the FGFR1 protein in GBM cell lines in vitro.CYY292 also exerted an effect on the conserved Ser777 residue of FGFR1.CYY292 dose-depen-dently inhibited cell proliferation,epithelial-mesenchymal transition,stemness,invasion,and migration in vitro by specifically targeting the FGFR1/AKT/Snail pathways in GBM cells,and this effect was prevented by pharmacological inhibitors and critical gene knockdown.In vivo experiments revealed that CYY292 inhibited U87MG tumor growth more effectively than AZD4547.CYY292 also efficiently reduced GBM cell proliferation and increased survival in orthotopic GBM models.This study further elucidates the function of FGFR1 in the GBM and reveals the effect of CYY292,which targets FGFR1,on downstream signaling pathways directly reducing GBM cell growth,invasion,and metastasis and thus impairing the recruitment,acti-vation,and function of immune cells.
查看更多>>摘要：Cancer stem cells(CSCs)are considered tumor-initiating cells and the main drivers of disease progression.Targeting these rare cancer cells,however,remains challenging with respect to therapeutic benefit.Here,we report the up-regulation of IL-13RA2 expression in colorectal cancer(CRC)tissues and spheroid cells.The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC.We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients.Biologically,recombinant IL-13(rIL-13)stimulation promoted the sphere formation,proliferation,and migration of CRC cells in vi-tro and enhanced tumorigenesis in vivo.This phenotype could be reversed by knocking down IL-13RA2.Mechanistically,IL-13 activated autophagy by inducing LC3Ⅰ/LC3Ⅱ transformation in CRC-CSCs,which was crucial for the biological functions of IL-13.We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein,enhancing the interaction of UBE3C and p53,thereby inducing the K48-linked ubiquitination of p53.In conclusion,the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination,adding an important layer to the connection between IL-13 and p53,which can be translated into novel targeted therapies.
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