Livin和Survivin在成人急性淋巴细胞白血病中的表达及临床意义
摘要
背景与目的：细胞凋亡是一种由基因控制的程序化死亡,对保持组织的健康和正常生长有十分重要意义。细胞凋亡受抑,将导致细胞生存期延长,有利于转化突变的细胞生长积聚,最终可致肿瘤的产生。细胞凋亡受细胞内源性基因、酶类和信号传导途径的调控。目前发现机体内存在两类影响细胞凋亡的基因,即促凋亡基因和抗凋亡基因。凋亡抑制蛋白(inhibitor of apoptosis proteins.IAPs)家族是近年来发现的具有抗凋亡作用的蛋白,其特殊的分子结构及强大的抑制细胞凋亡功能正日益引起人们的关注。IAPs主要通过抑制半胱氨酸天冬氨酸特异性蛋白酶(caspases)抑制凋亡。目前IAPs家族共发现XIAP、c-IAP1、c-IAP2、NIAP、Livin、Apollon、Survivin、ILP-28个成员。其中Livin和Survivin是新近发现的IAPs家族成员,也是近年来的研究热点。作为IAPs家族中最具表达特异性的两种凋亡抑制蛋白,国内外多项研究表明其可在多种肿瘤细胞中特异性高表达,而在正常终末分化组织中很少或不表达。有研究表明Livin和Survivin在肿瘤组织中的高表达和肿瘤的发生、发展、转移以及预后相关。目前国内外对于Survivin和Livin在白血病中的表达及其意义也进行了相应的研究。已有基础研究表明,Survivin和Livin基因在不同的血液肿瘤细胞中均有不同程度表达,但是体外试验结果不能直接反应复杂的生物活体的病理生理变化,更加不能如实体现相应疾病患者的病理生理改变。成人急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)是血液系统恶性肿瘤中治疗困难、预后极差的一类疾病。进一步探讨急性淋巴细胞白血病发病的分子生物机制有助于理解其发病机理,对寻找潜在的治疗靶点具有重要意义。但目前就成人急性淋巴细胞白血病患者中这两种基因的表达情况、临床意义及二者有无协同表达等问题尚未见研究报道。
本研究旨在通过检测Livin和Survivin在成人急性淋巴细胞白血病中的表达以及两者的相关性,以探讨Livin与Survivin在成人ALL发病机制中的作用,探讨两种基因对成人ALL疗效及预后的影响,进而为寻找潜在的治疗靶点提供基础依据。
方法：应用半定量逆转录-聚合酶链反应(semi-quantify reverse transcription polymerase chain reaction, RT-PCR)方法检测了95例成人ALL患者(包括52例初治ALL患者,23例治疗后复发的ALL患者以及20例完全缓解的ALL患者)的骨髓中的Livin及Survivin表达水平,以20例健康者作为正常对照(normal control,NC)组。对所得结果进行统计学分析,比较Livin和Survivin在成人ALL初治组、缓解组、复发组以及正常对照组中的表达有无差异,分析初治组Livin和Survivin表达率高低与临床疗效的关系；并分析Livin和Survivin在初治患者中的表达水平有无相关性。
结果：
1.初治组ALL患者初治时、诱导治疗第19天时Livin的表达阳性率分别为48.1%、36.7%,在复发组表达阳性率为47.8%,在正常对照组及缓解组表达阳性率均为O%(0／20)。初治组和复发组Livin的表达率比较无显著性差异(P>0.05),缓解组与正常对照组的表达率无差别,初治组、复发组与缓解组、正常对照组分别比较,则均有显著性差异(P<0.05)。在初治成人ALL患者中,Livin的表达与否与年龄、性别、分型(包括形态学分型和免疫学分型)、初诊时白细胞(white blood cell,WBC)水平均无统计学差异。可进行疗效评估的49例初治ALL患者中,Livin阳性表达患者完全缓解率为43.5%,Livin阴性表达患者中完全缓解率为80.8%,两组缓解率比较有显著性差异(P<0.05)。
2.初治组ALL患者初治时、诱导治疗第19天时Survivin的表达阳性率分别为61.5%、51.0%,在复发组表达阳性率为60.9%,在正常对照组表达阳性率为10.0%,在缓解组表达为阴性。初治组和复发组Survivin的表达率比较无显著性差异(P>0.05),缓解组与正常对照组的表达率比较无显著性差异(P>0.05),初治组、复发组与缓解组、正常对照组分别比较,则均有显著性差异(P<0.05)。在初治成人ALL患者中,Survivin的表达与否与年龄、性别、分型(包括形态学分型和免疫学分型)、初诊时WBC水平均无统计学差异。可进行疗效评估的49例初治ALL患者中,Survivin阳性表达患者完全缓解率为50.0%,Survivin阴性表达患者中完全缓解率为84.2%,两组缓解率比较有显著性差异(P<0.05)。
3.Livin和Survivin在ALL初治组中的表达不具有关联性(P>0.05)。
结论：初治组、复发组ALL患者Livin和Survivin表达水平明显高于正常对照组及缓解组,提示Livin和Survivin可能参与成人ALL的发生与发展；Livin和Survivin的表达与患者的年龄、性别、分型、初诊时白细胞水平无明显关联；Livin和Survivin阳性表达的成人ALL患者完全缓解率低于阴性表达的成人ALL患者,提示Livin和Survivin高表达可能是成人ALL预后不良指标,两者可能成为监测成人ALL预后的重要指标；Survivin和Livin两者在初治ALL患者中的表达无明显相关性,提示两者之间可能没有协同表达作用。
Background and Objective:Apoptosis or Programmed cell death,is an active mechanism of cell death controlling the development and homeostasis of multicellular organisms and inhibiting cancer cells.Tight regulation is required to ensure a delicate balance of life and death.Several types of molecules are known to interfere with apoptosis,for example,cellular gene,proteases and signaling pathways.Two apoptotic pathways have been described.One is initiated cellapoptosis;the other is antiapoptosis.The major regulators of caspases are the IAPs or inhibitors of apoptosis proteins.The IAPs include XIAP、c-IAP1、c-IAP2、NIAP、Livin、Apollon、Survivin、ILP-2.Livin and Survivin are two novel members of inhibitor of apoptosis proteins family.As the most specificity inhibitor of apoptosis proteins,many studies both home and abroad prove that they can express highly and specially in many kinds of tumors.But both Livin and Survivin are not detectable in most normal adult tissues.Their high expression associate with poor prognosis.These two genes serve as new targets for apoptosis-inducing therapy of cancer.But the research on the function is just on the beginning.The studies of the expression of Livin and Survivin in adult acute lymphoblastic leukemia and Clinical significance are not available.This study intended to investigate the expression and clinical significance of livin,survivin in adult acute lymphoblastic leukemia,and to discuss their affection in adult acute lymphoblastic leukemia.
Methods:The expression of Livin,Survivin mRNA were measured in bone marrow cells or peripheral blood cells from 95 adult patients with acute lymphoblastic leukemia (52 de novo acute lymphoblastic leukemia patients,23 relapsed patients and 20 continued complete remission patients)by semi-quantity reverse transcription polymers chain reaction (RT-PCR).20 healthy samples were selected as normal controls (NC).It was analysised by clinical samples that the expression of livin and survivin variants correlated with completed remission of newly diagnosed ALL.
Results:
1.Livin was expressed in 48.1% of initial treatment.36.7% of ALL being in the 19th day of inductive treatment,and in 47.8% of relapse ALL.There were no statistical significant differences regarding the frequency of livin expression respectively between the initial treatment ALL and the relapse patients(P>0.05).There were statistically significant differences between the patients of livin positive and negative(P<0.05). There were no statistically significant differences between the patients of livin with different clinical features(P>0.05).In the 49 of 52 patients who can evaluate the therapeutic efficacy, the CR rate in Livin+ ALL was significantly higher than in Livin- ALL group(P<0.05).
2.Survivin was expressed in 61.5% of initial treatment.51.0% of ALL being in the 19th day of inductive treatment,and in 60.9% of relapse ALL.There were no statistical significant differences regarding the frequency of survivin expression respectively between the initial treatment ALL and the relapse patients(P>0.05).There were statistically significant differences between the patients of survivin positive and negative(P<0.05).There were no statistically significant differences between the patients of survivin with different clinical features(P>0.05). In the 49 of 52 patients who can evaluate the therapeutic efficacy, the CR rate in survivin+ ALL was significantly higher than in survivin- ALL group(P<0.05).
3.Correlation analysis of livin and survivin mRNA:The results indicate that there was no correlation between the expression of livin and survivin in newly diagnosed adult ALL.
Conclusions:The level of livin and survivin in newly diagnosed adult ALL patients and relapse patients were significantly higher than that of normal controls,indicating that livin and survivin maybe involved in the pathogenesis and progression in ALL.There were no statistically significant differences between the patients of livin and survivin with different clinical features.The CR rate of livin-、survivin- group was higher than that of livin+、survivin+ cases,indicating that overexpression of livin or survivin predicts poor prognosis.There was no correlation between the expression of livin and survivin in newly diagnosed adult ALL.
本研究旨在通过检测Livin和Survivin在成人急性淋巴细胞白血病中的表达以及两者的相关性,以探讨Livin与Survivin在成人ALL发病机制中的作用,探讨两种基因对成人ALL疗效及预后的影响,进而为寻找潜在的治疗靶点提供基础依据。
方法：应用半定量逆转录-聚合酶链反应(semi-quantify reverse transcription polymerase chain reaction, RT-PCR)方法检测了95例成人ALL患者(包括52例初治ALL患者,23例治疗后复发的ALL患者以及20例完全缓解的ALL患者)的骨髓中的Livin及Survivin表达水平,以20例健康者作为正常对照(normal control,NC)组。对所得结果进行统计学分析,比较Livin和Survivin在成人ALL初治组、缓解组、复发组以及正常对照组中的表达有无差异,分析初治组Livin和Survivin表达率高低与临床疗效的关系；并分析Livin和Survivin在初治患者中的表达水平有无相关性。
结果：
1.初治组ALL患者初治时、诱导治疗第19天时Livin的表达阳性率分别为48.1%、36.7%,在复发组表达阳性率为47.8%,在正常对照组及缓解组表达阳性率均为O%(0／20)。初治组和复发组Livin的表达率比较无显著性差异(P>0.05),缓解组与正常对照组的表达率无差别,初治组、复发组与缓解组、正常对照组分别比较,则均有显著性差异(P<0.05)。在初治成人ALL患者中,Livin的表达与否与年龄、性别、分型(包括形态学分型和免疫学分型)、初诊时白细胞(white blood cell,WBC)水平均无统计学差异。可进行疗效评估的49例初治ALL患者中,Livin阳性表达患者完全缓解率为43.5%,Livin阴性表达患者中完全缓解率为80.8%,两组缓解率比较有显著性差异(P<0.05)。
2.初治组ALL患者初治时、诱导治疗第19天时Survivin的表达阳性率分别为61.5%、51.0%,在复发组表达阳性率为60.9%,在正常对照组表达阳性率为10.0%,在缓解组表达为阴性。初治组和复发组Survivin的表达率比较无显著性差异(P>0.05),缓解组与正常对照组的表达率比较无显著性差异(P>0.05),初治组、复发组与缓解组、正常对照组分别比较,则均有显著性差异(P<0.05)。在初治成人ALL患者中,Survivin的表达与否与年龄、性别、分型(包括形态学分型和免疫学分型)、初诊时WBC水平均无统计学差异。可进行疗效评估的49例初治ALL患者中,Survivin阳性表达患者完全缓解率为50.0%,Survivin阴性表达患者中完全缓解率为84.2%,两组缓解率比较有显著性差异(P<0.05)。
3.Livin和Survivin在ALL初治组中的表达不具有关联性(P>0.05)。
结论：初治组、复发组ALL患者Livin和Survivin表达水平明显高于正常对照组及缓解组,提示Livin和Survivin可能参与成人ALL的发生与发展；Livin和Survivin的表达与患者的年龄、性别、分型、初诊时白细胞水平无明显关联；Livin和Survivin阳性表达的成人ALL患者完全缓解率低于阴性表达的成人ALL患者,提示Livin和Survivin高表达可能是成人ALL预后不良指标,两者可能成为监测成人ALL预后的重要指标；Survivin和Livin两者在初治ALL患者中的表达无明显相关性,提示两者之间可能没有协同表达作用。
Background and Objective:Apoptosis or Programmed cell death,is an active mechanism of cell death controlling the development and homeostasis of multicellular organisms and inhibiting cancer cells.Tight regulation is required to ensure a delicate balance of life and death.Several types of molecules are known to interfere with apoptosis,for example,cellular gene,proteases and signaling pathways.Two apoptotic pathways have been described.One is initiated cellapoptosis;the other is antiapoptosis.The major regulators of caspases are the IAPs or inhibitors of apoptosis proteins.The IAPs include XIAP、c-IAP1、c-IAP2、NIAP、Livin、Apollon、Survivin、ILP-2.Livin and Survivin are two novel members of inhibitor of apoptosis proteins family.As the most specificity inhibitor of apoptosis proteins,many studies both home and abroad prove that they can express highly and specially in many kinds of tumors.But both Livin and Survivin are not detectable in most normal adult tissues.Their high expression associate with poor prognosis.These two genes serve as new targets for apoptosis-inducing therapy of cancer.But the research on the function is just on the beginning.The studies of the expression of Livin and Survivin in adult acute lymphoblastic leukemia and Clinical significance are not available.This study intended to investigate the expression and clinical significance of livin,survivin in adult acute lymphoblastic leukemia,and to discuss their affection in adult acute lymphoblastic leukemia.
Methods:The expression of Livin,Survivin mRNA were measured in bone marrow cells or peripheral blood cells from 95 adult patients with acute lymphoblastic leukemia (52 de novo acute lymphoblastic leukemia patients,23 relapsed patients and 20 continued complete remission patients)by semi-quantity reverse transcription polymers chain reaction (RT-PCR).20 healthy samples were selected as normal controls (NC).It was analysised by clinical samples that the expression of livin and survivin variants correlated with completed remission of newly diagnosed ALL.
Results:
1.Livin was expressed in 48.1% of initial treatment.36.7% of ALL being in the 19th day of inductive treatment,and in 47.8% of relapse ALL.There were no statistical significant differences regarding the frequency of livin expression respectively between the initial treatment ALL and the relapse patients(P>0.05).There were statistically significant differences between the patients of livin positive and negative(P<0.05). There were no statistically significant differences between the patients of livin with different clinical features(P>0.05).In the 49 of 52 patients who can evaluate the therapeutic efficacy, the CR rate in Livin+ ALL was significantly higher than in Livin- ALL group(P<0.05).
2.Survivin was expressed in 61.5% of initial treatment.51.0% of ALL being in the 19th day of inductive treatment,and in 60.9% of relapse ALL.There were no statistical significant differences regarding the frequency of survivin expression respectively between the initial treatment ALL and the relapse patients(P>0.05).There were statistically significant differences between the patients of survivin positive and negative(P<0.05).There were no statistically significant differences between the patients of survivin with different clinical features(P>0.05). In the 49 of 52 patients who can evaluate the therapeutic efficacy, the CR rate in survivin+ ALL was significantly higher than in survivin- ALL group(P<0.05).
3.Correlation analysis of livin and survivin mRNA:The results indicate that there was no correlation between the expression of livin and survivin in newly diagnosed adult ALL.
Conclusions:The level of livin and survivin in newly diagnosed adult ALL patients and relapse patients were significantly higher than that of normal controls,indicating that livin and survivin maybe involved in the pathogenesis and progression in ALL.There were no statistically significant differences between the patients of livin and survivin with different clinical features.The CR rate of livin-、survivin- group was higher than that of livin+、survivin+ cases,indicating that overexpression of livin or survivin predicts poor prognosis.There was no correlation between the expression of livin and survivin in newly diagnosed adult ALL.
引文
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[1]Douglas R,Green,John C,et al.Mitochondria and apoptosis. Science,1998,281:1309-1312.
[2]Kerr JF,Wyllie AH,Currie AR.Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics.Br J Cancer,1972,26(4):239-257.
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[5]LaCass EC,Baird S,Komeluk RG,et al.The inhibitors of apoptosis(IAPs) and their emering role in cancer. Oncogene,1998,17(25):3247-3259.
[6]Lin JH, Deng QHuang Q, et al.KIAP, a novel member ofthe inhibitor of apoptosis protein family,Biochem Biophys Res Commun,2000,279(3):820-831.
[7]Vucic D,Stennicke HR,Pisabarro MT,et al.ML-IAP,a novel inhibitor of apoptosis that is preferentially expressed in human melanomas.Curr Biol,2000,10(21):1359-1366.
[8]Kasof GM,Gomes BC.Livin,a novel inhibitor of apoptosis protein family member.J Biol Chem,2001,276(5):3238-3246.
[9]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.
[10]Lin JH,Deng G,Huang Q et al.KIAP,a novel member of the inhibitor apoptosis protein family.Biochem Biophys Res Com,2000,279(3):820-831.
[11]Hariu H,Hirohashi Y,Torigoe T,et al.Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family,Livin/ML-IAP in lung cancer.Clin cancer Res,2005,11:1000-1009.
[12]Ka H,Hunt JS.Temporal and spatial patterns of expression of inhibitor of apoptosis in human placentas.Am J Pathol,2003,163:413-422.
[13]Kartmann B,Roth D.Novel roles for mammalian septins:from vesicle trafficking to oncogenesis.J Cell Sci,2201,114:839-844.
[14]Tanabe H, Yagihashia, Tsujin, et al.Expression of survivin mRNA and livin mRNA in non-small-cell lung cancer.Lung Cancer,2004,46(3):299-304
[15]孙建国,廖荣霞,陈正堂,等。一种新的凋亡抑制蛋白Livin在非小细胞肺癌组织中的表达。重庆医学,2004,33：982-984.
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[17]Yagihashi A,Asanuma K, Tsuji N, et al.Detection of anti-livin antibody in gastrointestinal cancer patients. Clin Chem,2003,49(7):1206-1208.
[18]Yagihashi A,Asanuma K, Nakamura M, et al.Detection of anti-survivin antibody in gastrointestinal cancer patients.Clin Chem,2001,47(7) 1729-1731.
[19]Xiang Y, Yao H,Wang S,et al.Prognostic value of survivin and livin in nasopharyngeal carcinoma.Laryngoscope,2006,116(1):126-130.
[20]Kim DK,Alvarado CS,Abramowsky CR, et al.Expression of inhibitor of apoptosis Protein(IAP) livin by neuroblastoma cells:collelation with prognostic factor and outcome.Pediatric Dev Pathol.2005,8(6):621-629.
[21]Franklin MC,Kadkhodayan S,Aekerly H,et al.Structure and functionAnalysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP).Biochemistry,2003Jul,15;42(27):8223-8231.
[22]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.
[23]Qiuping Z,Jei X,Youxin J,et al.Selectively frequent expression of CXCR5 enhances resistance to apoptosis in CD8(+)CD34(+)T cells from patients with T-cell-lineage acute lymphocytic leukemia. Oncogene,2005,24(4):573-584.
[24]Crnkovic-Mertena I,Hoppe-Seyler F,Butz K.Induction of tumor cells by siRNA-mediated silencing of the Livin/ML-IAP/KIAP gene.Oncogene,2003,22 (51):8330-8335.
[25]Nachmias B,Ashhab Y,Buchotz,V,et al.Caspase-mediated cleavage converts livin from an antiapoptotic to a proapoptotic factor:implications for drug-resistant melanoma.Cancer Res,2003,63(19):6340-6349.
[26]Puri N, Eller MS,Byers HR,et al.Telomere-based DNA damage responses:a new approach to melanoma.FASEBJ,2004,18(12):1373-1381.
[27]Schmollinger JC,Vonderheide RH, Hoark M, et al.Melanoma inhibitor of apoptosis protein(ML-IAP) is a target for immune-mediated tumor destruction.Proc Natl Acad Sci USA,2003,100(6):3398-3403。
[28]Andersen MH, Reker S,Becker JC,et al.The melanoma inhibitor of apoptosis protein:a target for spontaneous cytotoxic T cell responses.J Invest Dermatol,2004,122(2):392-399.