Livin在非小细胞肺癌组织中的表达及临床意义
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摘要
背景:非小细胞肺癌的发生发展在分子水平一直以来都认为与凋亡相关。Livin是近来人类发现的凋亡抑制蛋白家族的成员,表达于多种实体肿瘤中,并参与其发生发展。目前,Livin在非小细胞肺癌中的研究才刚起步。
目的:Livin存在Livinα和Livinβ两个异构体。Livin主要通过抑制caspase3,7,9的活性,阻碍多途径诱导的细胞凋亡。已发现在多数肿瘤中表达Livin,与肿瘤发生、发展密切相关,并可能作为诱导肿瘤凋亡治疗的新靶点。本实验主要探讨凋亡抑制蛋白Livin在非小细胞肺癌(NSCLC)组织中的表达及其与NSCLC临床病理的关系。
方法:选择手术切除的48例非小细胞肺癌患者标本,癌旁组织、肺部良性病变组织以及正常肺组织标本各8例,采用实时定量逆转录聚合酶链式反应(real time qRT-PCR)检测NSCLC组织中Livin-mRNA的表达,Western-blot分析Livin蛋白的表达。实验结果用X±S表示,采用单因素方差分析,应用SPSS11.3进行统计学分析,探讨非小细胞肺癌组织中Livin蛋白的表达情况与病理类型、病理分期、分化程度、淋巴结转移和放化疗之间的关系。
结果Livin在非小细胞肺癌组织中表达,与病理分型、分化程度、TNM分期以及淋巴结转移无显著相关。在癌旁组织、良性病变组织与正常组织表达极低,实时qRT-PCR测得Livin-mRNA△△Ct值分别为12.520±0.417、12.761±0.365及12.492±0.334,术前经过放、化疗的肺癌组织中,Livin-mRNA (△△Ct值为0.074±0.318)较未接受术前放、化疗病例(△△Ct值为1.279±0.364 )Livin-mRNA表达明显增高,有显著统计学意义。Western-blot研究Livin蛋白的表达,在实时定量RT-PCR中测得△△Ct值小于1的样本,均能检测到Livin蛋白的表达,表达量的高低,与所测得的△△Ct值一致,即与Livin-mRNA表达的高低一致。而在正常肺组织,癌旁组织以及良性病变的组织中,未能检测到Livin蛋白的表达。
结论Livin在非小细胞肺癌组织中表达,与病理分型、分化程度、TNM分期以及淋巴结转移无显著相关,在放、化疗的NSCLC组织中,Livin表达更高,提示Livin基因的过度表达可能是肺癌本身固有的生物学特性之一,参与肺癌的发生发展,参与放、化疗抵抗,并可能成为肺癌抑制凋亡治疗的新靶点。
Background: It has been suggested that progression of non-small cell lung cancer may be regulated at the molecular level by a typical pattern of expression of genes involved in apoptosis. Recently, Livin belonging to the inhibitors of apoptosis (IAP) family, has been found to be expressed in most solid tumors, where its expression is suggested to have prognostic significance. No data are available concerning the significance of Livin in the progression of non-small cell lung cancer. Objective: Livin, including two isomers of Livinαand Livinβ, inhibits apoptosis mainly by inhibiting caspase activity of caspase 3,7,9. Livin has been found to be expressed in most solid tumors, where its expression is suggested to have prognostic significance,and may serve as a new target for treatment.Our study is to detect the expression of Livin in non-small cell lung cancer (NSCLC) and to explore the relationship between Livin expression and NSCLC histological types.
Methods: Seventy-two samples from the patients by means of surgery,were analysized in this experiment, of which NSCLC 48 cases, para-cancerous, benign disease lung tissues and normal lung tissues 8 cases respectively.Livin-mRNA and protein expression levels in NSCLC tissues were detected by real-time quantitative reverse transcriptase polymerase chain reaction (real-time qRT-PCR) and western-blot assay respectively.One-Way ANOVA analysis was performed for the comparison of data from the expression of livin gene, and SPSS11.3 were used for statistical analysis.
Results: Livin-mRNA and protein expressed in non-small cell lung cancer tissues, barely expressed in para-cancerous or benign disease or normal lung tissues . Livin expression has no significant relationship with clinically pathological characteristics of lung cancer patients. The Livin-mRNA△△Ct value was 12.520±0.417, 12.761±0.365 and 12.492±0.334 in para-cancerous, benign disease lung tissues and normal lung tissues respectively, it was higher in lung cancer tissues acceptted preoperative chemotherapy or radiotherapy (Livin-mRNA△△Ct value 0.074±0.318), which was considered to be statistical significance with that of not (Livin-mRNA△△Ct value 1.279±0.364 ). Livin protein expression levels in NSCLC tissues were detected by western-blot assay, with which livin protein expression could be detected while the△△Ct value of the samples were less than 1, and the expression levels related to the△△Ct value. Livin protein was not expressed in para-cancerous, benign disease or normal lung tissues.
Conclusion: Livin expressed in non-small cell lung cancer, had no significant relationship with clinically pathological characteristics of lung cancer patients. Livin expressed higher levels in NSCLC tissues while acceptting preoperative chemotherapy or radiotherapy. The overexpression of livin may be one of inherent biological characteristics of NSCLC, Livin gene may play a role in NSCLC development and in apoptosis resistance to chemotherapy or radiotherapy, and may serve as a new target for lung cancer diagnosis and treatment.
目的:Livin存在Livinα和Livinβ两个异构体。Livin主要通过抑制caspase3,7,9的活性,阻碍多途径诱导的细胞凋亡。已发现在多数肿瘤中表达Livin,与肿瘤发生、发展密切相关,并可能作为诱导肿瘤凋亡治疗的新靶点。本实验主要探讨凋亡抑制蛋白Livin在非小细胞肺癌(NSCLC)组织中的表达及其与NSCLC临床病理的关系。
方法:选择手术切除的48例非小细胞肺癌患者标本,癌旁组织、肺部良性病变组织以及正常肺组织标本各8例,采用实时定量逆转录聚合酶链式反应(real time qRT-PCR)检测NSCLC组织中Livin-mRNA的表达,Western-blot分析Livin蛋白的表达。实验结果用X±S表示,采用单因素方差分析,应用SPSS11.3进行统计学分析,探讨非小细胞肺癌组织中Livin蛋白的表达情况与病理类型、病理分期、分化程度、淋巴结转移和放化疗之间的关系。
结果Livin在非小细胞肺癌组织中表达,与病理分型、分化程度、TNM分期以及淋巴结转移无显著相关。在癌旁组织、良性病变组织与正常组织表达极低,实时qRT-PCR测得Livin-mRNA△△Ct值分别为12.520±0.417、12.761±0.365及12.492±0.334,术前经过放、化疗的肺癌组织中,Livin-mRNA (△△Ct值为0.074±0.318)较未接受术前放、化疗病例(△△Ct值为1.279±0.364 )Livin-mRNA表达明显增高,有显著统计学意义。Western-blot研究Livin蛋白的表达,在实时定量RT-PCR中测得△△Ct值小于1的样本,均能检测到Livin蛋白的表达,表达量的高低,与所测得的△△Ct值一致,即与Livin-mRNA表达的高低一致。而在正常肺组织,癌旁组织以及良性病变的组织中,未能检测到Livin蛋白的表达。
结论Livin在非小细胞肺癌组织中表达,与病理分型、分化程度、TNM分期以及淋巴结转移无显著相关,在放、化疗的NSCLC组织中,Livin表达更高,提示Livin基因的过度表达可能是肺癌本身固有的生物学特性之一,参与肺癌的发生发展,参与放、化疗抵抗,并可能成为肺癌抑制凋亡治疗的新靶点。
Background: It has been suggested that progression of non-small cell lung cancer may be regulated at the molecular level by a typical pattern of expression of genes involved in apoptosis. Recently, Livin belonging to the inhibitors of apoptosis (IAP) family, has been found to be expressed in most solid tumors, where its expression is suggested to have prognostic significance. No data are available concerning the significance of Livin in the progression of non-small cell lung cancer. Objective: Livin, including two isomers of Livinαand Livinβ, inhibits apoptosis mainly by inhibiting caspase activity of caspase 3,7,9. Livin has been found to be expressed in most solid tumors, where its expression is suggested to have prognostic significance,and may serve as a new target for treatment.Our study is to detect the expression of Livin in non-small cell lung cancer (NSCLC) and to explore the relationship between Livin expression and NSCLC histological types.
Methods: Seventy-two samples from the patients by means of surgery,were analysized in this experiment, of which NSCLC 48 cases, para-cancerous, benign disease lung tissues and normal lung tissues 8 cases respectively.Livin-mRNA and protein expression levels in NSCLC tissues were detected by real-time quantitative reverse transcriptase polymerase chain reaction (real-time qRT-PCR) and western-blot assay respectively.One-Way ANOVA analysis was performed for the comparison of data from the expression of livin gene, and SPSS11.3 were used for statistical analysis.
Results: Livin-mRNA and protein expressed in non-small cell lung cancer tissues, barely expressed in para-cancerous or benign disease or normal lung tissues . Livin expression has no significant relationship with clinically pathological characteristics of lung cancer patients. The Livin-mRNA△△Ct value was 12.520±0.417, 12.761±0.365 and 12.492±0.334 in para-cancerous, benign disease lung tissues and normal lung tissues respectively, it was higher in lung cancer tissues acceptted preoperative chemotherapy or radiotherapy (Livin-mRNA△△Ct value 0.074±0.318), which was considered to be statistical significance with that of not (Livin-mRNA△△Ct value 1.279±0.364 ). Livin protein expression levels in NSCLC tissues were detected by western-blot assay, with which livin protein expression could be detected while the△△Ct value of the samples were less than 1, and the expression levels related to the△△Ct value. Livin protein was not expressed in para-cancerous, benign disease or normal lung tissues.
Conclusion: Livin expressed in non-small cell lung cancer, had no significant relationship with clinically pathological characteristics of lung cancer patients. Livin expressed higher levels in NSCLC tissues while acceptting preoperative chemotherapy or radiotherapy. The overexpression of livin may be one of inherent biological characteristics of NSCLC, Livin gene may play a role in NSCLC development and in apoptosis resistance to chemotherapy or radiotherapy, and may serve as a new target for lung cancer diagnosis and treatment.
引文
[1] Kasof GM,Gomes BC.Livin,a novel inhibitor of apoptosis protein family member. J Biol Chem,2001,276(5):3238-3246.
[2] Vucic D, Stennicke HR, Pisabarro MT, et al.ML-IAP,a novel inhibitor of apoptosis that is preferentially expressedin human melanomas. Curr Biol , 2000 , 10 (21) :1359-1366
[3] Lin JH,Deng G,Huang Q,et al.KIAP,a novel member of the inhibitor of apoptosis protein family.Biochem Biophys Res Commun,2000,279(3): 820-831.
[4] Ashhab Y, Alian A, Polliack A,et al. Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett.2001,495(1-2):56-60
[5] Gary M,Kasof GM,Bruce C,et al.Livin,a novel inhibitor of apoptosis protein family member. Biochem J.2001,276(5):3238-3246
[6] Sanna MG, da Silva Correia J, Luo Y, et al. IAP suppression of apoptosis involves distint mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol, 2002,22:1753-1766
[7] Sanna MG, Duckett CS, Richter BW, et al. ILPIP, a novel antiapoptotic protein that enhances XIAP mediated activation of JNK1 and protection against apoptosis. J Biol Chem,2002,277:30454-30462
[8] Vucic D, Frankin MC, Walweber HJ , et al. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor:implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J, 2005, 385 (Pt 1): 11-20.
[9] Dukett CS. IAP proteins: sticking it to Smac.Biochem J,2005, 385(Pt 1): e1-2.
[10] Vucic D, Deshayes K, Ackerly H, et al. SAMC negatively regulates the anti-apoptotic activity of melanoma inhibitro of apoptosis(ML-IAP). Biochem J,2002,277:12275-12279
[11] Yagihashi A,Ohmura T,Asanuma K,et al.Detection of autoantibodies to survivin and livin in sera from patients with breast cancer.Clin Chim Acta,2005 Dec;362(1-2):125-130
[12] Yagihashi A,Asanuma K,Tsuji N,et al.Detection of anti-livin antibody in gastrointestinal cancer patients.Clin Chem,2003,49(7):1206-1208
[13] Xiang Y,Yao H,Wang S,et al. Prognostic value of Survivin and Livin innasopharyngeal carcinoma.Laryngoscope,2006,116(1):126-130
[14] Gazzaniga P, Gradilone A, Giuliani L,et al.Expression and prognostic significance of LIVIN, SURVIVIN and other apoptosis-related genes in the progression of superficial bladder cancer.Ann Oncol, 2003,14(1):85-90
[15] Qiuping Z,Jei X,Youxin J,et al.CC chemokine ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients with T-cell lineage acute and chronic lymphocytic leukemia by means of livin activation.Cancer Res,2004,64(20):7579-7587
[16] Tanabe H,Yagihashi A,Tsuji N,et al.Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer. Lung Cancer. 2004,46(3):299-304
[17] Mei ZZ, Sun ZX. Inhibitor of apoptosis proteins and the regulation of apoptosis.Foreign Medical Science of Genetics,1999,22(6):281-285
[18] Sun JG, Liao RX, Chen ZT, et al.Gene transfection of Livin isoforms into A549 cell line and its effect on cell growth and sensitivity to chemotherapy and radiotherapy.Zhonghua Jie He He Hu Xi Za Zhi,2005,28(12):836-840
[19] Crnkovic-Mertens I,Muley T,Meister M,et al. The anti-apoptotic livin gene is an important determinant for the apoptotic resistance of non-small cell lung cancer cells.Lung Cancer,2006,54(2):135-142.
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[12] Sanna MG, Duckett CS, Richter BW, et al. ILPIP, a novel antiapoptotic protein that enhances XIAP mediated activation of JNK1 and protection against apoptosis. J BiolChem,2002,277:30454-30462
[13] Vucic D, Frankin MC, Walweber HJ , et al. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor:implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J, 2005, 385 (Pt 1): 11-20.
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[25] Qiuping Z,Jei X,Youxin J,et al.CC chemokine ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients with T-cell lineage acute and chronic lymphocytic leukemia by means of livin activation.Cancer Res,2004,64(20):7579-7587
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[38] Yagihashi A,Ohmura T,Asanuma K,et al.Detection of autoantibodies to survivin and livin in sera from patients with breast cancer.Clin Chim Acta,2005 Dec;362(1-2):125-130
[39] Yagihashi A,Asanuma K,Tsuji N,et al.Detection of anti-livin antibody in gastrointestinal cancer patients.Clin Chem,2003,49(7):1206-1208
[40] Xiang Y,Yao H,Wang S,et al. Prognostic value of Survivin and Livin in nasopharyngeal carcinoma.Laryngoscope,2006,116(1):126-130
[2] Vucic D, Stennicke HR, Pisabarro MT, et al.ML-IAP,a novel inhibitor of apoptosis that is preferentially expressedin human melanomas. Curr Biol , 2000 , 10 (21) :1359-1366
[3] Lin JH,Deng G,Huang Q,et al.KIAP,a novel member of the inhibitor of apoptosis protein family.Biochem Biophys Res Commun,2000,279(3): 820-831.
[4] Ashhab Y, Alian A, Polliack A,et al. Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett.2001,495(1-2):56-60
[5] Gary M,Kasof GM,Bruce C,et al.Livin,a novel inhibitor of apoptosis protein family member. Biochem J.2001,276(5):3238-3246
[6] Sanna MG, da Silva Correia J, Luo Y, et al. IAP suppression of apoptosis involves distint mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol, 2002,22:1753-1766
[7] Sanna MG, Duckett CS, Richter BW, et al. ILPIP, a novel antiapoptotic protein that enhances XIAP mediated activation of JNK1 and protection against apoptosis. J Biol Chem,2002,277:30454-30462
[8] Vucic D, Frankin MC, Walweber HJ , et al. Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor:implications for Smac-dependent anti-apoptotic activity of ML-IAP. Biochem J, 2005, 385 (Pt 1): 11-20.
[9] Dukett CS. IAP proteins: sticking it to Smac.Biochem J,2005, 385(Pt 1): e1-2.
[10] Vucic D, Deshayes K, Ackerly H, et al. SAMC negatively regulates the anti-apoptotic activity of melanoma inhibitro of apoptosis(ML-IAP). Biochem J,2002,277:12275-12279
[11] Yagihashi A,Ohmura T,Asanuma K,et al.Detection of autoantibodies to survivin and livin in sera from patients with breast cancer.Clin Chim Acta,2005 Dec;362(1-2):125-130
[12] Yagihashi A,Asanuma K,Tsuji N,et al.Detection of anti-livin antibody in gastrointestinal cancer patients.Clin Chem,2003,49(7):1206-1208
[13] Xiang Y,Yao H,Wang S,et al. Prognostic value of Survivin and Livin innasopharyngeal carcinoma.Laryngoscope,2006,116(1):126-130
[14] Gazzaniga P, Gradilone A, Giuliani L,et al.Expression and prognostic significance of LIVIN, SURVIVIN and other apoptosis-related genes in the progression of superficial bladder cancer.Ann Oncol, 2003,14(1):85-90
[15] Qiuping Z,Jei X,Youxin J,et al.CC chemokine ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients with T-cell lineage acute and chronic lymphocytic leukemia by means of livin activation.Cancer Res,2004,64(20):7579-7587
[16] Tanabe H,Yagihashi A,Tsuji N,et al.Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer. Lung Cancer. 2004,46(3):299-304
[17] Mei ZZ, Sun ZX. Inhibitor of apoptosis proteins and the regulation of apoptosis.Foreign Medical Science of Genetics,1999,22(6):281-285
[18] Sun JG, Liao RX, Chen ZT, et al.Gene transfection of Livin isoforms into A549 cell line and its effect on cell growth and sensitivity to chemotherapy and radiotherapy.Zhonghua Jie He He Hu Xi Za Zhi,2005,28(12):836-840
[19] Crnkovic-Mertens I,Muley T,Meister M,et al. The anti-apoptotic livin gene is an important determinant for the apoptotic resistance of non-small cell lung cancer cells.Lung Cancer,2006,54(2):135-142.
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