Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better u...Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy.Here,we observed the nucleus accumulation of ZBTB20,a member of ZBTB-protein family,in the chondrocytes of early-stage OA.Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress,restored the balance of extracellular matrix anabolism and catabolism.The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation.Furthermore,the subcellular localization of ZBTB20 was modulated by the kinase LATS1.Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis,improving the abnormal behavior and moderating cartilage degeneration.The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.展开更多
Adipose-derived mesenchymal stem cells(ADSCs)represent a readily accessible and important source of mesenchymal stem cells(MSCs)capable of multilineage differentiation.The Hippo signaling pathway effector YAP has emer...Adipose-derived mesenchymal stem cells(ADSCs)represent a readily accessible and important source of mesenchymal stem cells(MSCs)capable of multilineage differentiation.The Hippo signaling pathway effector YAP has emerged as a pivotal regulator of stem cell fate,yet the specific molecular mechanism by which it modulates lipogenic differentiation of ADSCs has not been clearly defined.In this study,goat ADSCs(gADSCs)isolated from Albas goats in Inner Mongolia were used to investigate the role of YAP1 in adipogenic differentiation.Overexpression of YAP1 significantly promoted the differentiation of ADSCs into adipocytes,an effect accompanied by up-regulation of LATS2 and activation of the negative feedback loop of the Hippo signaling pathway.Elevated LATS2 expression induced YAP phosphorylation,leading to reduced nuclear levels of YAP and TAZ and their subsequent accumulation in the cytoplasm.YAP1 overexpression up-regulated LATS2 expression,which,in turn,enhanced the adipogenic differentiation of ADSCs.This pro-adipogenic effect of YAP1 was dependent on LATS2 kinase activity.These findings indicate that overexpression of YAP1 promotes ADSC adipogenesis by inducing LATS2 expression and activating the Hippo pathway negative feedback loop.Elucidating the molecular role of YAP in ADSC lipogenic differentiation holds great significance for regulating stem cell fate,treating metabolic disorders,and promoting hair follicle growth.展开更多
Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma ...Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.展开更多
基金supported by grants from the National Natural Science Foundation of China(82002351,82394442,82130070,82272442)funded by the Innovation Capability Support Program of Shaanxi Province(2024SF-LCZX-16)+2 种基金the Shaanxi Province Health Scientific Research Innovation Ability Promotion Plan(2024PT-12)the Independent Exploration and Innovation Project of Xi’an Jiaotong University(xzy012023121)the project of Xi’an Postdoctoral Innovation Base.
文摘Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy.Here,we observed the nucleus accumulation of ZBTB20,a member of ZBTB-protein family,in the chondrocytes of early-stage OA.Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress,restored the balance of extracellular matrix anabolism and catabolism.The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation.Furthermore,the subcellular localization of ZBTB20 was modulated by the kinase LATS1.Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis,improving the abnormal behavior and moderating cartilage degeneration.The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.
基金supported by the Joint Fund for Regional Innovation and Development of the National Natural Science Foundation of China(U23A20226)Science and Technology Planning Project of Inner Mongolia Autonomous Region(2023KYPT0014)。
文摘Adipose-derived mesenchymal stem cells(ADSCs)represent a readily accessible and important source of mesenchymal stem cells(MSCs)capable of multilineage differentiation.The Hippo signaling pathway effector YAP has emerged as a pivotal regulator of stem cell fate,yet the specific molecular mechanism by which it modulates lipogenic differentiation of ADSCs has not been clearly defined.In this study,goat ADSCs(gADSCs)isolated from Albas goats in Inner Mongolia were used to investigate the role of YAP1 in adipogenic differentiation.Overexpression of YAP1 significantly promoted the differentiation of ADSCs into adipocytes,an effect accompanied by up-regulation of LATS2 and activation of the negative feedback loop of the Hippo signaling pathway.Elevated LATS2 expression induced YAP phosphorylation,leading to reduced nuclear levels of YAP and TAZ and their subsequent accumulation in the cytoplasm.YAP1 overexpression up-regulated LATS2 expression,which,in turn,enhanced the adipogenic differentiation of ADSCs.This pro-adipogenic effect of YAP1 was dependent on LATS2 kinase activity.These findings indicate that overexpression of YAP1 promotes ADSC adipogenesis by inducing LATS2 expression and activating the Hippo pathway negative feedback loop.Elucidating the molecular role of YAP in ADSC lipogenic differentiation holds great significance for regulating stem cell fate,treating metabolic disorders,and promoting hair follicle growth.
基金Natural Science Foundation of Xinjiang Uygur Autonomous Region(2022D01C803).
文摘Objectives:Melanoma is a highly aggressive and metastatic form of cancer,and the role of exosomal microRNAs(miRNAs)in its progression remains largely unexplored.This study aimed to investigate the effects of melanoma cell-derived exosomal miR-424-5p on angiogenesis and its underlying mechanisms.Methods:Exosomes were isolated from melanoma cell lines A375 and A2058,and their effects on the proliferation,migration,and angiogenesis of human umbilical vein endothelial cells(HUVECs)were examined.The interaction between miR-424-5p and its target gene,large tumor suppressor kinase 2(LATS2),was analyzed using luciferase reporter assays and functional experiments.In vivo,tumor growth and angiogenesis were studied in a xenograft model using nude mice.Results:Melanoma cell-derived exosomes could be internalized by HUVECs,which promoted proliferation,migration,and angiogenesis.miR-424-5p was highly expressed in melanoma cells and their exosomes,and its inhibition in exosomes suppressed HUVEC proliferation,migration,and angiogenesis.LATS2 was identified as a direct target of miR-424-5p,and its silencing reversed the inhibitory effects of miR-424-5p inhibition on HUVEC functions.In vivo,exosomes derived from miR-424-5p-inhibited melanoma cells suppressed tumor growth and angiogenesis in xenograft models.Conclusions:Melanoma cell-derived exosomal miR-424-5p promotes angiogenesis by targeting LATS2,contributing to melanoma progression.Targeting the exosomal miR-424-5p/LATS2 axis could be a potential therapeutic strategy for melanoma.
