目的:研究抑癌基因孕激素和脂肪Q3受体(progestin and adipo Q receptor 3,PAQR3)在结直肠癌和肠道黏膜中的表达水平及临床病理意义。方法:利用TIMER数据库比较PAQR3在泛癌种肿瘤组织与对照组织中的差别,进而收集天津医科大学总医院2002...目的:研究抑癌基因孕激素和脂肪Q3受体(progestin and adipo Q receptor 3,PAQR3)在结直肠癌和肠道黏膜中的表达水平及临床病理意义。方法:利用TIMER数据库比较PAQR3在泛癌种肿瘤组织与对照组织中的差别,进而收集天津医科大学总医院2002年1月至2005年12月65例结直肠癌组织标本和41例肠道黏膜组织,采用免疫组织化学染色检测PAQR3蛋白在结直肠癌组织和肠道黏膜组织中的表达,并将65例结直肠癌分为高表达组和低表达组,探讨其表达与临床病理指标之间的关系及其对患者预后的影响。采用TIMER数据库分析PAQR3表达与免疫细胞浸润的关系,c Bio Portal数据库研究PAQR3表达改变对信号转导通路的影响。结果:TIMER数据库分析显示结直肠癌中PAQR3癌组织表达低于正常对照组织,免疫组化染色显示PAQR3蛋白在65例结直肠癌组织中阳性表达率显著低于正常黏膜组织(χ^(2)=21.165,P<0.001)。32例结直肠癌高表达PAQR3,33例结直肠癌呈PAQR3低表达,PAQR3高表达与肿瘤淋巴结转移、临床分期和远处转移呈负相关(χ^(2)=4.481,P=0.034,χ^(2)=8.855,P=0.031,χ^(2)=3.972,P=0.046)。Kaplan-Meier生存分析显示结直肠癌PAQR3高表达的患者总生存和无病生存均比低表达患者好(χ^(2)=10.305,P=0.001,χ^(2)=4.135,P=0.042)。TIMER数据库分析显示PAQR3低表达与免疫细胞浸润下降相关,富集分析表明PAQR3可能通过影响机体蛋白质合成及修饰影响结直肠癌代谢过程。结论:结直肠癌组织中PAQR3蛋白表达显著降低,其低表达与结直肠癌转移和免疫浸润降低密切相关。展开更多
背景与目的孕酮及脂联素受体家族成员3(progesterone and adiponectin receptor family member 3,PAQR3)是最新研究发现的抑癌基因,通过抑制细胞增殖、细胞恶性转化、抑制血管生成及肿瘤转移来影响肿瘤的发展。本研究旨在探讨PAQR3在肺...背景与目的孕酮及脂联素受体家族成员3(progesterone and adiponectin receptor family member 3,PAQR3)是最新研究发现的抑癌基因,通过抑制细胞增殖、细胞恶性转化、抑制血管生成及肿瘤转移来影响肿瘤的发展。本研究旨在探讨PAQR3在肺癌组织中的表达及其临床意义。方法选取天津医科大学总医院病理科2008年1月-2010年12月经病理明确诊断的106例肺癌组织标本作为实验组,同时取其癌旁正常组织作为对照。所有患者的诊断均经术后病理诊断证实,采用免疫组织化学方法检测PAQR3蛋白在肺癌组织和癌旁正常组织中的表达,并探讨其表达的临床意义。结果 PAQR3蛋白在肺癌组织中阳性表达率显著低于癌旁正常组织(P<0.01);PAQR3蛋白的阳性表达率与患者的性别、年龄、肿瘤大小无关,与患者的病理分型、分化程度、TNM分期和有无淋巴结转移具有相关性(P<0.05);Kaplan-Meier生存分析结果显示PAQR3蛋白阳性表达的患者5年生存率高于阴性表达的患者(P<0.05)。结论 PAQR3蛋白的表达量在肺癌组织中明显降低,提示PAQR3可能在肺癌的发病机制中发挥重要的作用。展开更多
目的探讨孕酮和脂联素受体3(Progestin And Adipo Q ReceptorⅢ,PAQR3)基因在胃癌组织中的甲基化状态及其临床意义。方法收集2015年3～9月经病理确诊的原发性胃癌及癌旁组织45对,采用甲基化特异性PCR法检测PAQR3基因启动子区甲基化水平...目的探讨孕酮和脂联素受体3(Progestin And Adipo Q ReceptorⅢ,PAQR3)基因在胃癌组织中的甲基化状态及其临床意义。方法收集2015年3～9月经病理确诊的原发性胃癌及癌旁组织45对,采用甲基化特异性PCR法检测PAQR3基因启动子区甲基化水平,免疫组化法检测PAQR3蛋白的表达,并分析其与患者肿瘤临床病理特征之间的关系。结果胃癌组织中PAQR3基因启动子甲基化率(44.44%,20/45)显著高于癌旁组织(8.89%,4/45,P<0.001),而PAQR3蛋白表达则较癌旁组织显著降低,两者间呈负相关(r=-0.478,P<0.01)。PAQR3基因启动子甲基化率及PAQR3蛋白的表达与肿瘤浸润深度、淋巴结转移、TNM分期相关(P<0.01)。结论 PAQR3基因启动子区高甲基化可能是引起胃癌组织PAQR3表达降低的重要原因,有望成为胃癌病情和预后评估的分子标记物以及表观遗传学治疗靶点。展开更多
目的初步探究孕激素和脂联素受体家族成员9(progestin and adipoQ receptor family member 9,PAQR9)对棕色脂肪产热及解偶联蛋白1(uncoupling protein 1,UCP1)表达的影响。方法选取C57BL/6J小鼠的白色脂肪组织(white adipose tissue,WAT...目的初步探究孕激素和脂联素受体家族成员9(progestin and adipoQ receptor family member 9,PAQR9)对棕色脂肪产热及解偶联蛋白1(uncoupling protein 1,UCP1)表达的影响。方法选取C57BL/6J小鼠的白色脂肪组织(white adipose tissue,WAT)、棕色脂肪组织(brown adipose tissue,BAT)及前棕色脂肪细胞系DE2-3和间充质干细胞C3H10T1/2细胞系进行研究。实时荧光定量PCR技术检测不同条件下PAQR9及UCP1的mRNA水平,蛋白免疫印迹法检测UCP1的蛋白质水平。实时荧光定量PCR技术和油红O染色法检测脂肪细胞的成脂分化情况。结果 C57BL/6J小鼠BAT中PAQR9的mRNA水平显著高于WAT。冷刺激诱导下,BAT和腹股沟皮下WAT中PAQR9的mRNA水平显著升高。DE2-3细胞诱导分化成熟即第6天时,PAQR9的mRNA水平显著高表达。在DE2-3细胞中过表达PAQR9,UCP1的mRNA水平显著上调,细胞耗氧量显著增加,而DE2-3细胞成脂分化功能无显著性差异。在DE2-3细胞中敲低PAQR9,UCP1的mRNA水平显著下调。在C3H10T1/2细胞第4~6天脂肪细胞分化成熟时,PAQR9的mRNA水平显著上调,在敲低PAQR9后UCP1蛋白质水平下调,而C3H10T1/2细胞成脂分化功能无显著性差异。结论 PAQR9能够促进棕色脂肪细胞产热,调控产热基因UCP1的表达。展开更多
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the ...The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.展开更多
CDK4 is crucial for Gl-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cycUns are pivotal for the timely and unidirectional progression of cell cycle. H...CDK4 is crucial for Gl-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cycUns are pivotal for the timely and unidirectional progression of cell cycle. However, how CDK4 itself is modulated by ubiquitin-mediated degradation has been elusive. Here we report that the steady-state level of CDK4 is controlled by PAQR4, a member of the progestin and adipoQ receptor family, and SKP2, an E3 ubiquitin ligase. Knockdown of PAQR4 leads to reduction of cell proliferation, accompanied by reduced protein level of CDK4. PAQR4 reduces polyubiquitination and degradation of CDK4. PAQR4 interacts with the C-terminal lobe of CDK4. On the other hand, SKP2 also interacts with the C-terminal lobe of CDK4 and enhances polyubiquitination and degradation of CDK4. importantly, PAQR4 and SKP2 bind to the same region in CDK4, and PAQR4 competes with SKP2 for the binding, thereby abrogating SKP2-mediated ubiquitination of CDK4. Using a two-stage DMBA/TPA-induced skin cancer model, we find that PAQR4-deleted mice are resistant to chemical carcinogen-induced tumor formation. Collectively, our findings reveal that the steady-state level of CDK4 is controlled by the antagonistic actions between PAQR4 and SKP2, contributing to modulation of cell proliferation and tumorigenesis.展开更多
文摘目的:研究抑癌基因孕激素和脂肪Q3受体(progestin and adipo Q receptor 3,PAQR3)在结直肠癌和肠道黏膜中的表达水平及临床病理意义。方法:利用TIMER数据库比较PAQR3在泛癌种肿瘤组织与对照组织中的差别,进而收集天津医科大学总医院2002年1月至2005年12月65例结直肠癌组织标本和41例肠道黏膜组织,采用免疫组织化学染色检测PAQR3蛋白在结直肠癌组织和肠道黏膜组织中的表达,并将65例结直肠癌分为高表达组和低表达组,探讨其表达与临床病理指标之间的关系及其对患者预后的影响。采用TIMER数据库分析PAQR3表达与免疫细胞浸润的关系,c Bio Portal数据库研究PAQR3表达改变对信号转导通路的影响。结果:TIMER数据库分析显示结直肠癌中PAQR3癌组织表达低于正常对照组织,免疫组化染色显示PAQR3蛋白在65例结直肠癌组织中阳性表达率显著低于正常黏膜组织(χ^(2)=21.165,P<0.001)。32例结直肠癌高表达PAQR3,33例结直肠癌呈PAQR3低表达,PAQR3高表达与肿瘤淋巴结转移、临床分期和远处转移呈负相关(χ^(2)=4.481,P=0.034,χ^(2)=8.855,P=0.031,χ^(2)=3.972,P=0.046)。Kaplan-Meier生存分析显示结直肠癌PAQR3高表达的患者总生存和无病生存均比低表达患者好(χ^(2)=10.305,P=0.001,χ^(2)=4.135,P=0.042)。TIMER数据库分析显示PAQR3低表达与免疫细胞浸润下降相关,富集分析表明PAQR3可能通过影响机体蛋白质合成及修饰影响结直肠癌代谢过程。结论:结直肠癌组织中PAQR3蛋白表达显著降低,其低表达与结直肠癌转移和免疫浸润降低密切相关。
文摘背景与目的孕酮及脂联素受体家族成员3(progesterone and adiponectin receptor family member 3,PAQR3)是最新研究发现的抑癌基因,通过抑制细胞增殖、细胞恶性转化、抑制血管生成及肿瘤转移来影响肿瘤的发展。本研究旨在探讨PAQR3在肺癌组织中的表达及其临床意义。方法选取天津医科大学总医院病理科2008年1月-2010年12月经病理明确诊断的106例肺癌组织标本作为实验组,同时取其癌旁正常组织作为对照。所有患者的诊断均经术后病理诊断证实,采用免疫组织化学方法检测PAQR3蛋白在肺癌组织和癌旁正常组织中的表达,并探讨其表达的临床意义。结果 PAQR3蛋白在肺癌组织中阳性表达率显著低于癌旁正常组织(P<0.01);PAQR3蛋白的阳性表达率与患者的性别、年龄、肿瘤大小无关,与患者的病理分型、分化程度、TNM分期和有无淋巴结转移具有相关性(P<0.05);Kaplan-Meier生存分析结果显示PAQR3蛋白阳性表达的患者5年生存率高于阴性表达的患者(P<0.05)。结论 PAQR3蛋白的表达量在肺癌组织中明显降低,提示PAQR3可能在肺癌的发病机制中发挥重要的作用。
文摘目的初步探究孕激素和脂联素受体家族成员9(progestin and adipoQ receptor family member 9,PAQR9)对棕色脂肪产热及解偶联蛋白1(uncoupling protein 1,UCP1)表达的影响。方法选取C57BL/6J小鼠的白色脂肪组织(white adipose tissue,WAT)、棕色脂肪组织(brown adipose tissue,BAT)及前棕色脂肪细胞系DE2-3和间充质干细胞C3H10T1/2细胞系进行研究。实时荧光定量PCR技术检测不同条件下PAQR9及UCP1的mRNA水平,蛋白免疫印迹法检测UCP1的蛋白质水平。实时荧光定量PCR技术和油红O染色法检测脂肪细胞的成脂分化情况。结果 C57BL/6J小鼠BAT中PAQR9的mRNA水平显著高于WAT。冷刺激诱导下,BAT和腹股沟皮下WAT中PAQR9的mRNA水平显著升高。DE2-3细胞诱导分化成熟即第6天时,PAQR9的mRNA水平显著高表达。在DE2-3细胞中过表达PAQR9,UCP1的mRNA水平显著上调,细胞耗氧量显著增加,而DE2-3细胞成脂分化功能无显著性差异。在DE2-3细胞中敲低PAQR9,UCP1的mRNA水平显著下调。在C3H10T1/2细胞第4~6天脂肪细胞分化成熟时,PAQR9的mRNA水平显著上调,在敲低PAQR9后UCP1蛋白质水平下调,而C3H10T1/2细胞成脂分化功能无显著性差异。结论 PAQR9能够促进棕色脂肪细胞产热,调控产热基因UCP1的表达。
基金supported by research grants from the National Natural Science Foundation of China (No.81770816 and 81973375)the Key Project of Natural Science Foundation of Guangdong Province,China (No.2017A030311036)+1 种基金Seed Program of Guangdong Province (No.2017B090903004,China)Guangdong Provincial Key Field and Program Project (No.2020B1111100004,China)。
文摘The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes.Progestin and adipoQ receptor 3(PAQR3),a key regulator of inflammation and metabolism,can negatively regulate the PI3 K/AKT signaling pathway.Here,we report that gentiopicroside(GPS),the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa,decreased lipid synthesis and increased glucose utilization in palmitic acid(PA) treated HepG2 cells.Additionally,GPS improved glycolipid metabolism in streptozotocin(STZ) treated high-fat diet(HFD)-induced diabetic mice.Our findings revealed that GPS promoted the activation of the PI3 K/AKT axis by facilitating DNA-binding protein 2(DDB2)-mediated PAQR3 ubiquitinated degradation.Moreover,results of surface plasmon resonance(SPR),microscale thermophoresis(MST) and thermal shift assay(TSA) indicated that GPS directly binds to PAQR3.Results of molecular docking and cellular thermal shift assay(CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40,Asp42,Glu69,Tyr125 and Ser129,and spatially inhibited the interaction between PAQR3 and the PI3 K catalytic subunit(P110α) to restore the PI3 K/AKT signaling pathway.In summary,our study identified GPS,which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway,as a potential drug candidate for the treatment of diabetes.
文摘CDK4 is crucial for Gl-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cycUns are pivotal for the timely and unidirectional progression of cell cycle. However, how CDK4 itself is modulated by ubiquitin-mediated degradation has been elusive. Here we report that the steady-state level of CDK4 is controlled by PAQR4, a member of the progestin and adipoQ receptor family, and SKP2, an E3 ubiquitin ligase. Knockdown of PAQR4 leads to reduction of cell proliferation, accompanied by reduced protein level of CDK4. PAQR4 reduces polyubiquitination and degradation of CDK4. PAQR4 interacts with the C-terminal lobe of CDK4. On the other hand, SKP2 also interacts with the C-terminal lobe of CDK4 and enhances polyubiquitination and degradation of CDK4. importantly, PAQR4 and SKP2 bind to the same region in CDK4, and PAQR4 competes with SKP2 for the binding, thereby abrogating SKP2-mediated ubiquitination of CDK4. Using a two-stage DMBA/TPA-induced skin cancer model, we find that PAQR4-deleted mice are resistant to chemical carcinogen-induced tumor formation. Collectively, our findings reveal that the steady-state level of CDK4 is controlled by the antagonistic actions between PAQR4 and SKP2, contributing to modulation of cell proliferation and tumorigenesis.
