肾上腺素受体β1亚型（ADRB1）在肿瘤恶病质脂肪消耗过程中的作用和机制研究
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摘要
第一部分脂肪分解通路受体在肿瘤恶病质病人脂肪组织中的表达及临床意义
目的：检测肿瘤恶病质病人和对照组病人脂肪细胞膜上脂肪分解通路受体的表达情况,分析其与肿瘤恶病质病人脂肪分解增强的关系。
方法：共入组34例病人,其中肿瘤恶病质12例、肿瘤对照13例、良性对照9例,术中收集腹部皮下脂肪组织标本。Real-time PCR方法检测肾上腺素受体β1亚型(ADRB1)、肾上腺素受体β2亚型(ADRB2)、肾上腺素受体β3亚型(ADRB3)、肾上腺素受体α2C亚型(ADRA2C)、心房钠尿肽受体A(NPRA)、胰岛素受体(INSR),以及激素敏感性酯酶(HSL)的mRNA水平。Western blot测定ADRB1和HSL的蛋白水平；免疫组织荧光方法进行ADRB1蛋白定位。结果：肿瘤恶病质病人脂肪组织中ADRB1和HSL的mRNA相对水平比肿瘤对照组和良性对照组升高约50%(P=0.022；P=0.013),而其他脂肪分解通路受体的mRNA相对水平没有显著改变。恶病质组ADRB1蛋白相对表达量分别是肿瘤对照组的1.5倍及良性对照组的3倍(P<0.001；P<0.001)。免疫组织荧光检测证实ADRB1蛋白表达于脂肪细胞膜。恶病质组HSL蛋白表达量是两个对照组的2-2.5倍(P<0.001；P=0.005)。ADRB1和HSL的蛋白相对表达水平呈正相关(r=0.474,P=0.005)。ADRB1蛋白相对表达水平与甘油三酯(triglyceride,TG)分解率呈正相关(r=0.406,P=0.002；r=0.435,P=0.01)。
结论：肿瘤恶病质病人脂肪细胞膜上ADRB1蛋白表达增加,与HSL表达增强和TG分解率增强呈正相关,提示ADRB1过表达可能通过激活脂肪分解通路导致肿瘤恶病质病人脂肪消耗。
第二部分基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达模型的建立
目的：利用慢病毒载体,建立基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达细胞模型。
方法：利用DNA重组技术将人类ADRB1 cDNA克隆片段和慢病毒载体质粒(pLVX-IRES-ZsGreen1)连接；将重组载体和慢病毒包装质粒共转染293T细胞,在细胞中进行病毒包装；包装好的假病毒颗粒被分泌到细胞外的培养基中,质粒感染48小时收集富含慢病毒颗粒的细胞上清液,直接用于感染3T3-L1前脂肪细胞株,将ADRB1基因稳定转染进3T3-L1前脂肪细胞株。最后利用GFP流式细胞分选技术筛选稳定转染细胞株进行培养,从而建立了基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达模型。
结果：Western blot检测证明,ADRB1过表达组的ADRB1蛋白相对水平较转空病毒对照组(mock组)显著增高,证明了含有ADRB1基因的慢病毒载体质粒构建、慢病毒包装、慢病毒感染3T3-L1细胞、稳定转染细胞株筛选步骤均正确。ADRB1基因随病毒DNA整合进宿主细胞基因组,使ADRB1蛋白在3T3-L1前脂肪细胞膜上稳定过表达,基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达模型构建成功。
结论：建立了基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达细胞模型,使之模拟肿瘤恶病质病人脂肪细胞的特征性改变,为进一步研究ADRB1过表达在肿瘤恶病质脂肪消耗过程中的作用奠定了模型基础。
第三部分脂肪细胞中ADRB1基因过表达对脂肪消耗的影响及其分子机制
目的：利用分子生物学实验手段验证临床标本检测实验所揭示的现象,进一步研究ADRB1过表达在肿瘤恶病质脂肪消耗过程中的作用及其分子机制。
方法：设立control组、mock组、ADRB1过表达组、抑制剂干预组。利用MDI方案诱导ADRB1稳定过表达的3T3-L1前脂肪细胞模型分化为成熟脂肪细胞,通过油红O染色实验及Western blot检测422(aP2)蛋白水平,研究ADRB1过表达对脂肪细胞分化的影响。利用Western blot方法检测ADRB1和HSL蛋白水平,研究ADRB1过表达对TG分解通路的影响；通过Western blot检测脂肪合成通路关键酶脂肪酸合成酶(fatty acid synthase, FAS)的蛋白水平,研究ADRB1过表达对TG合成过程的影响。
结果:ADRB1过表达组中ADRB1蛋白相对水平显著高于control组和mock组,证实ADRB1过表达模型构建成功。油红O染色实验和422(aP2)蛋白水平检测证实,control组和mock组细胞能够分化,而ADRB1过表达组中脂肪细胞完全无法分化,该作用可被ADRB1抑制剂逆转。与control组和mock组相比,ADRB1过表达组中HSL蛋白相对水平显著增强、即脂肪分解通路激活,该作用可被ADRB1抑制剂逆转；ADRB1过表达组中FAS蛋白相对水平显著降低、即脂肪合成受到抑制,该作用可被ADRB1抑制剂逆转。
结论：脂肪细胞中ADRB1过表达通过抑制TG合成、刺激TG分解、抑制脂肪细胞分化,导致肿瘤恶病质病人脂肪消耗。
Part I Implication of Lipolysis-pathway Receptors in Lipolysis in Patients with Cancer Cachexia
Objectives:To detect the expression of lipolysis-pathway receptors of adipocytes and to elucidate their implications in cancer cachectic patients.
Methods:A total of 34 patients were recruited, including 12 cancer cachexia patients, 13 cancer controls and 9 nonmalignant controls. Gene expression levels of (31-adrenergic receptor (ADRB1),β2-adrenergic receptor (ADRB2), (33-adrenergic receptor (ADRB3), a2C-adrenergic receptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose samples of 34 patients by Real-time PCR. Protein levels of AD RBI and HSL were detected by Western blot. ADRB1 Localization was performed by immunofluorescence staining.
Results:mRNA levels of both ADRB1 and HSL were-50% elevated selectively in the cachexia group (P=0.022; P=0.013), whereas mRNA levels of the other receptors remained unchanged. ADRB1 protein level showed a 1.5 fold and 3 fold increase in the cachexia group as compared with cancer controls and nonmalignant controls (P< 0.001; P<0.001). ADRB1 was confirmed as a membrane protein in adipocytes by immuno fluorescence staining. HSL protein expression was 2-2.5 fold increased selectively in cancer cachexia group (P<0.001; P=0.005). There was a positive correlation between protein level of ADRB 1 and HSL (r=0.474, P=0.005), as well as between ADRB1 level and lipolytic rate (r=0.406, P=0.002; r=0.435, P=0.01).
Conclusion:We found increased ADRB1 expression in adipocytes of cancer cachectic patients, which is positively correlated with elevated HSL expression and increased lipolysis rate in this pathological setting.
Part II Establishment of Cell Model with Human ADRB1 Gene Overexpression Based on 3T3-L1 Cell Line
Objectives:To establish an adipocyte model with stable overexpression of human ADRB1 gene based on 3T3-L1 cell line with lentiviral vector.
Methods:Human ADRB1 cDNA and lentiviral vector (pLVX-IRES-ZsGreenl) were ligated using recombinant DNA technology. The recombinant vector and packaging plasmids were co-transfected into 293T cells for virus packaging. Packed virus particles were secreted into the medium, which was collected 48 hours after transfection and applied for infection, through which ADRB1 gene were stably transfected into 3T3-L1 preadipocyte cell line. Finally, stably transfected cell line was selected with fluorescence-activated cell sorting (FACS).
Results:All procedures were correct including cloning of ADRB1 construct, lentiviral packaging and infection, screening of stably transfected 3T3-L1 cell line. ADRB1 gene was integrated into host cell genome with viral DNA, so that ADRB1 protein was stably overexpressed on 3T3-L1 preadipocyte cell membrane. Western blot displayed a significantly elevated protein level of ADRB1 compared with the mock group, which demonstrated that model establishment is correct.
Conclusion:We have established an adipocyte model with stable overexpression of ADRB1 based on 3T3-L1 cell line, which laid the foundation for further studies by mimicing the pathological changes of adipocytes in cancer cachectic patients.
Part III Implications of ADRB1 Gene Overexpression in Fat Consumption in Cancer Cachexia
Objectives:to further investigate the implications of ADRB1 gene overexpression in fat consumption in cancer cachexia.
Methods:An overall study of overexpression of ADRB1 gene in fat consumption in cancer cachexia and the potential mechanism was carried out through inducing 3T3-L1 prcadipocyte with ADRB1 overexpression differentiate into adipocyte by MDI-based criteria. In the study, its impact on lipolysis was evaluated by detecting protein level of HSL; that in adipocyte differentiation evaluated by oil red staining and detection of protein level of 422(aP2), molecular marker in the process; that in triglyceride (TG) synthesis evaluated by the detection of protein level of fatty acid synthase, key enzyme in fat synthesis pathway.
Results:3T3-L1 differentiated completely in the control and mock group, but didn't in ADRB1 overexpression group, which could be attenuated by ADRB1 inhibitor with dose-effect relationship. Increased protein level of HSL and decreased level of FAS were detected in ADRB1 overexpression group, compared with the control and mock group, which could be attenuated by ADRB1 inhibitor.
Conclusion:ADRB1 gene overexpression leads to fat consumption in cancer cachexia through inhibition of TG synthesis, stimulation of TG breakdown, and inhibition of adipocyte differentiation.
目的：检测肿瘤恶病质病人和对照组病人脂肪细胞膜上脂肪分解通路受体的表达情况,分析其与肿瘤恶病质病人脂肪分解增强的关系。
方法：共入组34例病人,其中肿瘤恶病质12例、肿瘤对照13例、良性对照9例,术中收集腹部皮下脂肪组织标本。Real-time PCR方法检测肾上腺素受体β1亚型(ADRB1)、肾上腺素受体β2亚型(ADRB2)、肾上腺素受体β3亚型(ADRB3)、肾上腺素受体α2C亚型(ADRA2C)、心房钠尿肽受体A(NPRA)、胰岛素受体(INSR),以及激素敏感性酯酶(HSL)的mRNA水平。Western blot测定ADRB1和HSL的蛋白水平；免疫组织荧光方法进行ADRB1蛋白定位。结果：肿瘤恶病质病人脂肪组织中ADRB1和HSL的mRNA相对水平比肿瘤对照组和良性对照组升高约50%(P=0.022；P=0.013),而其他脂肪分解通路受体的mRNA相对水平没有显著改变。恶病质组ADRB1蛋白相对表达量分别是肿瘤对照组的1.5倍及良性对照组的3倍(P<0.001；P<0.001)。免疫组织荧光检测证实ADRB1蛋白表达于脂肪细胞膜。恶病质组HSL蛋白表达量是两个对照组的2-2.5倍(P<0.001；P=0.005)。ADRB1和HSL的蛋白相对表达水平呈正相关(r=0.474,P=0.005)。ADRB1蛋白相对表达水平与甘油三酯(triglyceride,TG)分解率呈正相关(r=0.406,P=0.002；r=0.435,P=0.01)。
结论：肿瘤恶病质病人脂肪细胞膜上ADRB1蛋白表达增加,与HSL表达增强和TG分解率增强呈正相关,提示ADRB1过表达可能通过激活脂肪分解通路导致肿瘤恶病质病人脂肪消耗。
第二部分基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达模型的建立
目的：利用慢病毒载体,建立基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达细胞模型。
方法：利用DNA重组技术将人类ADRB1 cDNA克隆片段和慢病毒载体质粒(pLVX-IRES-ZsGreen1)连接；将重组载体和慢病毒包装质粒共转染293T细胞,在细胞中进行病毒包装；包装好的假病毒颗粒被分泌到细胞外的培养基中,质粒感染48小时收集富含慢病毒颗粒的细胞上清液,直接用于感染3T3-L1前脂肪细胞株,将ADRB1基因稳定转染进3T3-L1前脂肪细胞株。最后利用GFP流式细胞分选技术筛选稳定转染细胞株进行培养,从而建立了基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达模型。
结果：Western blot检测证明,ADRB1过表达组的ADRB1蛋白相对水平较转空病毒对照组(mock组)显著增高,证明了含有ADRB1基因的慢病毒载体质粒构建、慢病毒包装、慢病毒感染3T3-L1细胞、稳定转染细胞株筛选步骤均正确。ADRB1基因随病毒DNA整合进宿主细胞基因组,使ADRB1蛋白在3T3-L1前脂肪细胞膜上稳定过表达,基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达模型构建成功。
结论：建立了基于3T3-L1前脂肪细胞株的人类ADRB1基因稳定过表达细胞模型,使之模拟肿瘤恶病质病人脂肪细胞的特征性改变,为进一步研究ADRB1过表达在肿瘤恶病质脂肪消耗过程中的作用奠定了模型基础。
第三部分脂肪细胞中ADRB1基因过表达对脂肪消耗的影响及其分子机制
目的：利用分子生物学实验手段验证临床标本检测实验所揭示的现象,进一步研究ADRB1过表达在肿瘤恶病质脂肪消耗过程中的作用及其分子机制。
方法：设立control组、mock组、ADRB1过表达组、抑制剂干预组。利用MDI方案诱导ADRB1稳定过表达的3T3-L1前脂肪细胞模型分化为成熟脂肪细胞,通过油红O染色实验及Western blot检测422(aP2)蛋白水平,研究ADRB1过表达对脂肪细胞分化的影响。利用Western blot方法检测ADRB1和HSL蛋白水平,研究ADRB1过表达对TG分解通路的影响；通过Western blot检测脂肪合成通路关键酶脂肪酸合成酶(fatty acid synthase, FAS)的蛋白水平,研究ADRB1过表达对TG合成过程的影响。
结果:ADRB1过表达组中ADRB1蛋白相对水平显著高于control组和mock组,证实ADRB1过表达模型构建成功。油红O染色实验和422(aP2)蛋白水平检测证实,control组和mock组细胞能够分化,而ADRB1过表达组中脂肪细胞完全无法分化,该作用可被ADRB1抑制剂逆转。与control组和mock组相比,ADRB1过表达组中HSL蛋白相对水平显著增强、即脂肪分解通路激活,该作用可被ADRB1抑制剂逆转；ADRB1过表达组中FAS蛋白相对水平显著降低、即脂肪合成受到抑制,该作用可被ADRB1抑制剂逆转。
结论：脂肪细胞中ADRB1过表达通过抑制TG合成、刺激TG分解、抑制脂肪细胞分化,导致肿瘤恶病质病人脂肪消耗。
Part I Implication of Lipolysis-pathway Receptors in Lipolysis in Patients with Cancer Cachexia
Objectives:To detect the expression of lipolysis-pathway receptors of adipocytes and to elucidate their implications in cancer cachectic patients.
Methods:A total of 34 patients were recruited, including 12 cancer cachexia patients, 13 cancer controls and 9 nonmalignant controls. Gene expression levels of (31-adrenergic receptor (ADRB1),β2-adrenergic receptor (ADRB2), (33-adrenergic receptor (ADRB3), a2C-adrenergic receptor (ADRA2C), natriuretic peptide receptor A (NPRA), insulin receptor (INSR), and HSL were determined in adipose samples of 34 patients by Real-time PCR. Protein levels of AD RBI and HSL were detected by Western blot. ADRB1 Localization was performed by immunofluorescence staining.
Results:mRNA levels of both ADRB1 and HSL were-50% elevated selectively in the cachexia group (P=0.022; P=0.013), whereas mRNA levels of the other receptors remained unchanged. ADRB1 protein level showed a 1.5 fold and 3 fold increase in the cachexia group as compared with cancer controls and nonmalignant controls (P< 0.001; P<0.001). ADRB1 was confirmed as a membrane protein in adipocytes by immuno fluorescence staining. HSL protein expression was 2-2.5 fold increased selectively in cancer cachexia group (P<0.001; P=0.005). There was a positive correlation between protein level of ADRB 1 and HSL (r=0.474, P=0.005), as well as between ADRB1 level and lipolytic rate (r=0.406, P=0.002; r=0.435, P=0.01).
Conclusion:We found increased ADRB1 expression in adipocytes of cancer cachectic patients, which is positively correlated with elevated HSL expression and increased lipolysis rate in this pathological setting.
Part II Establishment of Cell Model with Human ADRB1 Gene Overexpression Based on 3T3-L1 Cell Line
Objectives:To establish an adipocyte model with stable overexpression of human ADRB1 gene based on 3T3-L1 cell line with lentiviral vector.
Methods:Human ADRB1 cDNA and lentiviral vector (pLVX-IRES-ZsGreenl) were ligated using recombinant DNA technology. The recombinant vector and packaging plasmids were co-transfected into 293T cells for virus packaging. Packed virus particles were secreted into the medium, which was collected 48 hours after transfection and applied for infection, through which ADRB1 gene were stably transfected into 3T3-L1 preadipocyte cell line. Finally, stably transfected cell line was selected with fluorescence-activated cell sorting (FACS).
Results:All procedures were correct including cloning of ADRB1 construct, lentiviral packaging and infection, screening of stably transfected 3T3-L1 cell line. ADRB1 gene was integrated into host cell genome with viral DNA, so that ADRB1 protein was stably overexpressed on 3T3-L1 preadipocyte cell membrane. Western blot displayed a significantly elevated protein level of ADRB1 compared with the mock group, which demonstrated that model establishment is correct.
Conclusion:We have established an adipocyte model with stable overexpression of ADRB1 based on 3T3-L1 cell line, which laid the foundation for further studies by mimicing the pathological changes of adipocytes in cancer cachectic patients.
Part III Implications of ADRB1 Gene Overexpression in Fat Consumption in Cancer Cachexia
Objectives:to further investigate the implications of ADRB1 gene overexpression in fat consumption in cancer cachexia.
Methods:An overall study of overexpression of ADRB1 gene in fat consumption in cancer cachexia and the potential mechanism was carried out through inducing 3T3-L1 prcadipocyte with ADRB1 overexpression differentiate into adipocyte by MDI-based criteria. In the study, its impact on lipolysis was evaluated by detecting protein level of HSL; that in adipocyte differentiation evaluated by oil red staining and detection of protein level of 422(aP2), molecular marker in the process; that in triglyceride (TG) synthesis evaluated by the detection of protein level of fatty acid synthase, key enzyme in fat synthesis pathway.
Results:3T3-L1 differentiated completely in the control and mock group, but didn't in ADRB1 overexpression group, which could be attenuated by ADRB1 inhibitor with dose-effect relationship. Increased protein level of HSL and decreased level of FAS were detected in ADRB1 overexpression group, compared with the control and mock group, which could be attenuated by ADRB1 inhibitor.
Conclusion:ADRB1 gene overexpression leads to fat consumption in cancer cachexia through inhibition of TG synthesis, stimulation of TG breakdown, and inhibition of adipocyte differentiation.
引文
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