Ⅰ型胰岛素样生长因子受体（type I insulin-like growthfactor receptor，IGF-IR）是细胞生长分化的重要调节因子，可介导丝裂信号、防御各种凋亡损伤，并为一些细胞类型转化所必需。IGF－1R在多种肿瘤包括神经母细胞瘤中被发现异常表...Ⅰ型胰岛素样生长因子受体（type I insulin-like growthfactor receptor，IGF-IR）是细胞生长分化的重要调节因子，可介导丝裂信号、防御各种凋亡损伤，并为一些细胞类型转化所必需。IGF－1R在多种肿瘤包括神经母细胞瘤中被发现异常表达，并被认为是潜在的肿瘤治疗靶点。展开更多
Objective: To explore the mechanism by which ghrelin regulates insulin sensitivity through modulation of miR-455-5p in hepatic cells. Methods: HepG2 cells were treated with or without DAG (1 μM). Glucose consumption,...Objective: To explore the mechanism by which ghrelin regulates insulin sensitivity through modulation of miR-455-5p in hepatic cells. Methods: HepG2 cells were treated with or without DAG (1 μM). Glucose consumption, intracellular glycogen content, phosphorylation of PI3K and Akt stimulated by insulin, expression of miR-455-5p, as well as IGF-1R protein level were analyzed. In addition, bioinformatic analysis, dual luciferase reporter assay, miR- 455-5p mimic or inhibitor treatment was conducted to investigate the molecular mechanisms. Results: High glucose treatment upregulated miR-455-5p expression but reduced glucose consumption and glycogen content. DAG reversed the effect of high glucose on glucose metabolism, increased protein level of IGF-1R and phosphorylation of PI3K/Akt stimulated by insulin, as well as downregulated miR-455-5p expression. Bioinformatic analysis indicated IGF-1R was the target of miR-455-5p. Dual luciferase reporter assay, as well as transfection with miR-455-5p mimic/inhibitor confirmed that DAG activated IGF-1R/PI3K/Akt signaling via inhibiting miR-455-5p. Conclusion: DAG improves insulin resistance via miR-455-5p- mediated activation of IGF-1R/PI3K/Akt system, suggesting that suppression of miR-455-5p or activation of DAG may be potential targets for T2DM therapy.展开更多
Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/...Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF- 2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.展开更多
目的探讨乳腺癌组织T细胞分化蛋白2(mal T-cell differentiation protein 2,MAL2)、胰岛素样生长因子1受体(insulin like growth factor 1 receptor,IGF-1R)蛋白表达与病理特征及预后的相关性。方法选取营口市中心医院2015年3月~2016年...目的探讨乳腺癌组织T细胞分化蛋白2(mal T-cell differentiation protein 2,MAL2)、胰岛素样生长因子1受体(insulin like growth factor 1 receptor,IGF-1R)蛋白表达与病理特征及预后的相关性。方法选取营口市中心医院2015年3月~2016年3月收治的131例乳腺癌患者,采用免疫组织化学法检测乳腺癌患者癌旁正常组织和癌组织MAL2和IGF-1R蛋白表达水平,分析MAL2和IGF-1R蛋白水平与不同病理特点及预后的关系,并采用COX比例风险回归模型分析乳腺癌患者预后影响因素。结果乳腺癌患者癌组织MAL2(77.86%),IGF-1R蛋白(80.15%)阳性率显著高于癌旁正常组织(17.56%,21.37%),差异有统计学意义(χ^(2)=95.482,90.540,均P<0.05);在不同乳腺癌TMN分期以及分化程度上MAL2和IGF-1R蛋白阳性表达率差异均有统计学意义(χ^(2)_(MAL2)=33.545,16.188,χ^(2)_(IGF-1R)=6.533,12.422,均P<0.001)。131例乳腺癌患者随访期间,预后较差患者59例,预后良好患者72例;预后较差组患者MAL2(94.92%),IGF-1R(91.53%)蛋白阳性表达率显著高于预后良好组(36.11%,41.67%),差异均有统计学意义(χ^(2)=18.110,8.727,均P<0.05)。中低分化、III~IV期、MAL2蛋白阳性表达和IGF-1R蛋白阳性表达是患者不良预后的危险因素(P<0.05)。结论MAL2和IGF-1R蛋白在乳腺癌组织中具有较高的表达水平,且与乳腺癌患者TMN分期和分化程度具有明显的相关性,可能是患者不良预后的危险因素之一。展开更多
Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1...Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis(DOP).Serum from patients with or without DOP was collected to measure the IGF-1 R level using enzyme-linked immunosorbent assay(ELISA).Rats were given streptozotocin following a four-week high-fat diet induction(DOP group),or received vehicle after the same period of a normal diet(control group).Dual energy X-ray absorption,a biomechanics test,and hematoxylin-eosin(HE)staining were performed to evaluate bone mass,bone strength,and histomorphology,respectively,in vertebrae.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were performed to measure the total and phosphorylation levels of IGF-1 R,glycogen synthase kinase-3β(GSK-3β),andβ-catenin.The serum IGF-1 R level was much higher in patients with DOP than in controls.DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group.HE staining showed that the histomorphology of DOP vertebrae was seriously impaired,which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae.PCR analysis demonstrated that IGF-1 R mRNA expression was significantly up-regulated,and western blotting detection showed that phosphorylation levels of IGF-1 R,GSK-3β,andβ-catenin were enhanced in DOP rat vertebrae.Our results suggest that the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of DOP.This may contribute to development of the underlying therapeutic target for DOP.展开更多
文摘Ⅰ型胰岛素样生长因子受体（type I insulin-like growthfactor receptor，IGF-IR）是细胞生长分化的重要调节因子，可介导丝裂信号、防御各种凋亡损伤，并为一些细胞类型转化所必需。IGF－1R在多种肿瘤包括神经母细胞瘤中被发现异常表达，并被认为是潜在的肿瘤治疗靶点。
基金Changshu Science and Technology Plan(Social Development)Project(No.CS202130)Key Project of Changshu No.2 People’s Hospital(No.CSEY2021007)。
文摘Objective: To explore the mechanism by which ghrelin regulates insulin sensitivity through modulation of miR-455-5p in hepatic cells. Methods: HepG2 cells were treated with or without DAG (1 μM). Glucose consumption, intracellular glycogen content, phosphorylation of PI3K and Akt stimulated by insulin, expression of miR-455-5p, as well as IGF-1R protein level were analyzed. In addition, bioinformatic analysis, dual luciferase reporter assay, miR- 455-5p mimic or inhibitor treatment was conducted to investigate the molecular mechanisms. Results: High glucose treatment upregulated miR-455-5p expression but reduced glucose consumption and glycogen content. DAG reversed the effect of high glucose on glucose metabolism, increased protein level of IGF-1R and phosphorylation of PI3K/Akt stimulated by insulin, as well as downregulated miR-455-5p expression. Bioinformatic analysis indicated IGF-1R was the target of miR-455-5p. Dual luciferase reporter assay, as well as transfection with miR-455-5p mimic/inhibitor confirmed that DAG activated IGF-1R/PI3K/Akt signaling via inhibiting miR-455-5p. Conclusion: DAG improves insulin resistance via miR-455-5p- mediated activation of IGF-1R/PI3K/Akt system, suggesting that suppression of miR-455-5p or activation of DAG may be potential targets for T2DM therapy.
文摘Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF- 2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.
文摘目的探讨乳腺癌组织T细胞分化蛋白2(mal T-cell differentiation protein 2,MAL2)、胰岛素样生长因子1受体(insulin like growth factor 1 receptor,IGF-1R)蛋白表达与病理特征及预后的相关性。方法选取营口市中心医院2015年3月~2016年3月收治的131例乳腺癌患者,采用免疫组织化学法检测乳腺癌患者癌旁正常组织和癌组织MAL2和IGF-1R蛋白表达水平,分析MAL2和IGF-1R蛋白水平与不同病理特点及预后的关系,并采用COX比例风险回归模型分析乳腺癌患者预后影响因素。结果乳腺癌患者癌组织MAL2(77.86%),IGF-1R蛋白(80.15%)阳性率显著高于癌旁正常组织(17.56%,21.37%),差异有统计学意义(χ^(2)=95.482,90.540,均P<0.05);在不同乳腺癌TMN分期以及分化程度上MAL2和IGF-1R蛋白阳性表达率差异均有统计学意义(χ^(2)_(MAL2)=33.545,16.188,χ^(2)_(IGF-1R)=6.533,12.422,均P<0.001)。131例乳腺癌患者随访期间,预后较差患者59例,预后良好患者72例;预后较差组患者MAL2(94.92%),IGF-1R(91.53%)蛋白阳性表达率显著高于预后良好组(36.11%,41.67%),差异均有统计学意义(χ^(2)=18.110,8.727,均P<0.05)。中低分化、III~IV期、MAL2蛋白阳性表达和IGF-1R蛋白阳性表达是患者不良预后的危险因素(P<0.05)。结论MAL2和IGF-1R蛋白在乳腺癌组织中具有较高的表达水平,且与乳腺癌患者TMN分期和分化程度具有明显的相关性,可能是患者不良预后的危险因素之一。
基金Project supported by the National Natural Science Foundation of China(Nos.81774338 and 81674000)the Natural Science Foundation of Guangdong Province(No.2016A030313645)+1 种基金the Science and Technology Projects of Guangdong Province(No.2016A020226006)the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(2018),China
文摘Insulin-like growth factor-1 receptor(IGF-1 R)is involved in both glucose and bone metabolism.IGF-1 R signaling regulates the canonical Wnt/β-catenin signaling pathway.In this study,we investigated whether the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of diabetic osteoporosis(DOP).Serum from patients with or without DOP was collected to measure the IGF-1 R level using enzyme-linked immunosorbent assay(ELISA).Rats were given streptozotocin following a four-week high-fat diet induction(DOP group),or received vehicle after the same period of a normal diet(control group).Dual energy X-ray absorption,a biomechanics test,and hematoxylin-eosin(HE)staining were performed to evaluate bone mass,bone strength,and histomorphology,respectively,in vertebrae.Quantitative real-time polymerase chain reaction(qRT-PCR)and western blotting were performed to measure the total and phosphorylation levels of IGF-1 R,glycogen synthase kinase-3β(GSK-3β),andβ-catenin.The serum IGF-1 R level was much higher in patients with DOP than in controls.DOP rats exhibited strikingly reduced bone mass and attenuated compression strength of the vertebrae compared with the control group.HE staining showed that the histomorphology of DOP vertebrae was seriously impaired,which manifested as decreased and thinned trabeculae and increased lipid droplets within trabeculae.PCR analysis demonstrated that IGF-1 R mRNA expression was significantly up-regulated,and western blotting detection showed that phosphorylation levels of IGF-1 R,GSK-3β,andβ-catenin were enhanced in DOP rat vertebrae.Our results suggest that the IGF-1 R/β-catenin signaling axis plays a role in the pathogenesis of DOP.This may contribute to development of the underlying therapeutic target for DOP.
