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
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
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
BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heter...BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heterogeneity of this disease.LATS2,a tumor suppressor gene involved in the Hippo signaling pathway,has been identified as a potential prognostic biomarker in gastric cancer.AIM To construct and validate a nomogram model that includes LATS2 expression to predict the survival prognosis of advanced gastric cancer patients following ra-dical surgery,and compare its predictive performance with traditional TNM staging.METHODS A retrospective analysis of 245 advanced gastric cancer patients from the Fourth Hospital of Hebei Medical University was conducted.The patients were divided into a training group(171 patients)and a validation group(74 patients)to deve-lop and test our prognostic model.The performance of the model was determined using C-indices,receiver operating characteristic curves,calibration plots,and decision curves.RESULTS The model demonstrated a high predictive accuracy with C-indices of 0.829 in the training set and 0.862 in the validation set.Area under the curve values for three-year and five-year survival prediction were significantly robust,suggesting an excellent discrimination ability.Calibration plots confirmed the high concordance between the predictions and actual survival outcomes.CONCLUSION We developed a nomogram model incorporating LATS2 expression,which significantly outperformed conven-tional TNM staging in predicting the prognosis of advanced gastric cancer patients postsurgery.This model may serve as a valuable tool for individualized patient management,allowing for more accurate stratification and im-proved clinical outcomes.Further validation in larger patient cohorts will be necessary to establish its generaliza-bility and clinical utility.展开更多
The Leser-Trélat sign is an uncommon dermatological manifestation characterized by the sudden and rapid onset of multiple seborrheic keratoses, variably distributed across the body. Its clinical significance lies...The Leser-Trélat sign is an uncommon dermatological manifestation characterized by the sudden and rapid onset of multiple seborrheic keratoses, variably distributed across the body. Its clinical significance lies in its association with underlying neoplasms, primarily solid tumors such as gastric, colon, and breast adenocarcinomas. Less frequently, it has been linked to hematological and lymphoid malignancies, reinforcing its role as a paraneoplastic syndrome. These lesions may appear as an isolated finding or alongside other systemic signs, emphasizing the importance of a comprehensive diagnostic approach to identify potential associated neoplasms. We present the case of a 72-year-old male patient who sought medical attention for constitutional symptoms, fever, nocturnal chills, and abdominal distension. Sudden-onset brown seborrheic and keratotic lesions were noted on his chest, back, abdomen, axillary, and cervical regions. Following evaluation, the patient was diagnosed with chronic myeloid leukemia. Given his advanced age and clinical condition, a palliative approach was chosen due to the high risk of complications with chemotherapy, and the patient was subsequently discharged. This case highlights the importance of recognizing the Leser-Trélat sign as a critical clinical marker for occult neoplasms. Its identification should prompt a thorough evaluation, particularly in patients with systemic symptoms, as it may provide the key to early diagnosis and optimized therapeutic planning.展开更多
目的:研究CD59分子在LAT(Linker for activated T cells)介导的T系淋巴细胞活化中所起的作用。方法:构建LAT-GFP融合蛋白,以逆转录病毒为载体转染Jurkat细胞,建立稳定转染细胞株(Jurkat-GFP)。分别使用CD59抗体刺激和pSUPER-siCD59干扰...目的:研究CD59分子在LAT(Linker for activated T cells)介导的T系淋巴细胞活化中所起的作用。方法:构建LAT-GFP融合蛋白,以逆转录病毒为载体转染Jurkat细胞,建立稳定转染细胞株(Jurkat-GFP)。分别使用CD59抗体刺激和pSUPER-siCD59干扰质粒(GFP标记)沉默Jurkat-GFP细胞。免疫荧光观察CD59和LAT分子在细胞膜的表达和定位;MTT比色法检测细胞增殖率的变化;Western blot检测LAT活化信号转导通路中相关蛋白分子磷酸化水平。结果:荧光显微镜下可见Jurkat-GFP细胞绿色荧光表达于细胞膜,转染干扰质粒后细胞膜和细胞质均有绿色荧光表达。激光共聚焦显微镜下可见CD59抗体刺激前CD59和LAT分子均匀分布于细胞膜,且转染干扰质粒的Jurkat-GFP细胞CD59表达量下降。CD59抗体刺激后CD59分子和LAT分子点状聚集共定位于细胞膜。MTT结果表明相对于正常Jurkat-GFP细胞,抗体活化后细胞增殖速率明显升高(P>0.05),而电转干扰质粒后细胞生长减慢。Western blot结果表明,CD59抗体刺激后细胞ZAP-70、LCK、PLC-r总蛋白表达无明显差异(P>0.05),而磷酸化蛋白表达显著增高(P<0.05)。结论:抗体活化后细胞膜上CD59和LAT分子聚集并共定位于细胞膜,且细胞信号转导通路下游分子磷酸化水平增高,进一步证实CD59分子经抗体活化后可促进LAT介导的T细胞信号转导。展开更多
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.
文摘BACKGROUND Gastric cancer is a leading cause of cancer-related deaths worldwide.Prognostic assessments are typically based on the tumor-node-metastasis(TNM)staging system,which does not account for the molecular heterogeneity of this disease.LATS2,a tumor suppressor gene involved in the Hippo signaling pathway,has been identified as a potential prognostic biomarker in gastric cancer.AIM To construct and validate a nomogram model that includes LATS2 expression to predict the survival prognosis of advanced gastric cancer patients following ra-dical surgery,and compare its predictive performance with traditional TNM staging.METHODS A retrospective analysis of 245 advanced gastric cancer patients from the Fourth Hospital of Hebei Medical University was conducted.The patients were divided into a training group(171 patients)and a validation group(74 patients)to deve-lop and test our prognostic model.The performance of the model was determined using C-indices,receiver operating characteristic curves,calibration plots,and decision curves.RESULTS The model demonstrated a high predictive accuracy with C-indices of 0.829 in the training set and 0.862 in the validation set.Area under the curve values for three-year and five-year survival prediction were significantly robust,suggesting an excellent discrimination ability.Calibration plots confirmed the high concordance between the predictions and actual survival outcomes.CONCLUSION We developed a nomogram model incorporating LATS2 expression,which significantly outperformed conven-tional TNM staging in predicting the prognosis of advanced gastric cancer patients postsurgery.This model may serve as a valuable tool for individualized patient management,allowing for more accurate stratification and im-proved clinical outcomes.Further validation in larger patient cohorts will be necessary to establish its generaliza-bility and clinical utility.
文摘The Leser-Trélat sign is an uncommon dermatological manifestation characterized by the sudden and rapid onset of multiple seborrheic keratoses, variably distributed across the body. Its clinical significance lies in its association with underlying neoplasms, primarily solid tumors such as gastric, colon, and breast adenocarcinomas. Less frequently, it has been linked to hematological and lymphoid malignancies, reinforcing its role as a paraneoplastic syndrome. These lesions may appear as an isolated finding or alongside other systemic signs, emphasizing the importance of a comprehensive diagnostic approach to identify potential associated neoplasms. We present the case of a 72-year-old male patient who sought medical attention for constitutional symptoms, fever, nocturnal chills, and abdominal distension. Sudden-onset brown seborrheic and keratotic lesions were noted on his chest, back, abdomen, axillary, and cervical regions. Following evaluation, the patient was diagnosed with chronic myeloid leukemia. Given his advanced age and clinical condition, a palliative approach was chosen due to the high risk of complications with chemotherapy, and the patient was subsequently discharged. This case highlights the importance of recognizing the Leser-Trélat sign as a critical clinical marker for occult neoplasms. Its identification should prompt a thorough evaluation, particularly in patients with systemic symptoms, as it may provide the key to early diagnosis and optimized therapeutic planning.
文摘目的:研究CD59分子在LAT(Linker for activated T cells)介导的T系淋巴细胞活化中所起的作用。方法:构建LAT-GFP融合蛋白,以逆转录病毒为载体转染Jurkat细胞,建立稳定转染细胞株(Jurkat-GFP)。分别使用CD59抗体刺激和pSUPER-siCD59干扰质粒(GFP标记)沉默Jurkat-GFP细胞。免疫荧光观察CD59和LAT分子在细胞膜的表达和定位;MTT比色法检测细胞增殖率的变化;Western blot检测LAT活化信号转导通路中相关蛋白分子磷酸化水平。结果:荧光显微镜下可见Jurkat-GFP细胞绿色荧光表达于细胞膜,转染干扰质粒后细胞膜和细胞质均有绿色荧光表达。激光共聚焦显微镜下可见CD59抗体刺激前CD59和LAT分子均匀分布于细胞膜,且转染干扰质粒的Jurkat-GFP细胞CD59表达量下降。CD59抗体刺激后CD59分子和LAT分子点状聚集共定位于细胞膜。MTT结果表明相对于正常Jurkat-GFP细胞,抗体活化后细胞增殖速率明显升高(P>0.05),而电转干扰质粒后细胞生长减慢。Western blot结果表明,CD59抗体刺激后细胞ZAP-70、LCK、PLC-r总蛋白表达无明显差异(P>0.05),而磷酸化蛋白表达显著增高(P<0.05)。结论:抗体活化后细胞膜上CD59和LAT分子聚集并共定位于细胞膜,且细胞信号转导通路下游分子磷酸化水平增高,进一步证实CD59分子经抗体活化后可促进LAT介导的T细胞信号转导。
