livin和caspase-3在喉鳞状细胞癌中的表达以及相关性研究
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摘要
目的研究livin蛋白和半胱氨酸天冬氨酸特异性蛋白酶-3（caspase-3）蛋白在喉鳞状细胞癌组织中的表达以及二者的相关性。
方法选取43例经术前病理活检及HE染色病理证实为喉鳞状细胞癌的组织（首次入院的患者，未进行放、化疗及免疫药物等抗肿瘤治疗措施），并同时选取43例OSAHS患者的喉黏膜组织标本作为对照组。然后采用免疫组织化学法检测livin蛋白和caspase-3蛋白在喉鳞状细胞癌组织和对照组喉黏膜组织中的表达情况，同时并分析两者的相关性。采用SPSS16.0统计软件进行卡方检验、Fisher确切概率法以及用Spearman相关分析来进行统计学处理，取a=0.05为检验水准，P<0.05为差异有统计学意义，P<0.01为差异有显著统计学意义。
结果①喉鳞癌组织中livin阳性率74.42%, caspase-3阳性率41.86%，与对照组喉粘膜组织比较均差异有统计学意义(P<0.05)。②Livin蛋白的表达与喉鳞癌的临床分期、病理分化程度之间有统计学意义(P<0.05)，与患者年龄、性别及淋巴结转移情况这三个因素之间无统计学意义(P＞0.05)。③caspase-3蛋白表达在喉鳞癌组织中与患者年龄、性别、临床分期、病理分化程度及有无淋巴结转移这五个因素之间无统计学意义(P＞0.05)。④livin蛋白表达和caspase-3蛋白表达情况用Spearman进行统计学分析，发现在喉鳞癌组织中Livin表达和Caspase-3表达呈负相关关系。
结论①livin在LSCC组织中高表达，且其表达与喉鳞状细胞癌的临床分期、病理分型相关。提示Livin蛋白的表达可能参与了喉鳞状细胞癌的发生、发展过程。②caspase-3在LSCC组织中低表达，提示Caspase-3蛋白的表达可能参与了喉鳞状细胞癌的发生过程。③livin表达与Caspases表达在喉鳞状细胞癌中呈负相关关系，提示caspase-3可能受livin抑制调节，二者共同参与了喉鳞状细胞癌的发病机制。
Objective To detect the expression of Livin and cysteine asp-artate-specific proteases-3(Caspase-3) protein in laryngeal squamous cellcarcinoma, and their correlation.
Methods To Select43cases of laryngeal squamous cell carcinomaconfirmed by preoperative biopsy and HE staining pathology or ganizations(for the first time admitted patients, not the anti-tumor treatment ofradiotherapy and chemotherapy and immunosuppressive drugs),and at the sametime to select43cases of laryngeal mucosa tissue of patients with OSAHS as acontrol group. And immunohistochemical assay were performed to detect theLivin protein and Caspase-3protein expression in laryngeal squamous cellcarcinoma and control group in the situation.Then the laboratory data wereanalyzed of the correlation between the two gene. We used the SPSS16.0asStatistic analysis software and were statistically analyzed using Chi-squaretest，Fisher’s exat test and Spearman correlation analysis, take a=0.05for theinspection level, P <0.05was considered statistically significant, P <0.01asstatistically significant difference.
Results①The Livin expression positive rate was74.42%in Laryngealsquamous cell carcinoma and41.86%positive rate of Caspase-3.As comparedwith control group laryngeal mucosa difference was statistically significant(P<0.05).②The Livin protein expression was related to clinicalstage,pathological differentiation of laryngeal squamous cell carcinoma (P <005). But between patient age, gender, lymphoid metastasis these factors wasnot significant (P>0.05)；③The Caspase-3protein expression was no related topatient age, gender, clinical stage, pathology differentiation degree and lymphoid metastasis these five factors were not significant (P>0.05).④TheSpeannan rank correlation analysis method was used to analyze the correlationof Livin and Caspase.It showed that the expression of Livin was negativerelated to that of Caspase-3in Laryngeal squamous cell carcinoma.
Conclusion①The expression of Livin was significantly high inLaryngeal squamous cell carcinoma.And it expression was related to clinicalstage,pathological differentiation of laryngeal squamous cell carcinoma. Thehigh expression of Livin may indicate that it involved in the occurrence anddevelopment of laryngeal squamous cell carcinoma.②Caspases-3with lowexpression in LSCC suggest that it may be involved in the process of Laryngealsquamous cell carcinoma.③The expressions of Livin and Caspases-3inlaryngeal squamous cell carcinoma showed negative correlation. This showedthat caspase-3activation may be affected by the Livin protein regulation,bothinvolved in the pathogenesis of laryngeal squamous cell carcinoma.
方法选取43例经术前病理活检及HE染色病理证实为喉鳞状细胞癌的组织（首次入院的患者，未进行放、化疗及免疫药物等抗肿瘤治疗措施），并同时选取43例OSAHS患者的喉黏膜组织标本作为对照组。然后采用免疫组织化学法检测livin蛋白和caspase-3蛋白在喉鳞状细胞癌组织和对照组喉黏膜组织中的表达情况，同时并分析两者的相关性。采用SPSS16.0统计软件进行卡方检验、Fisher确切概率法以及用Spearman相关分析来进行统计学处理，取a=0.05为检验水准，P<0.05为差异有统计学意义，P<0.01为差异有显著统计学意义。
结果①喉鳞癌组织中livin阳性率74.42%, caspase-3阳性率41.86%，与对照组喉粘膜组织比较均差异有统计学意义(P<0.05)。②Livin蛋白的表达与喉鳞癌的临床分期、病理分化程度之间有统计学意义(P<0.05)，与患者年龄、性别及淋巴结转移情况这三个因素之间无统计学意义(P＞0.05)。③caspase-3蛋白表达在喉鳞癌组织中与患者年龄、性别、临床分期、病理分化程度及有无淋巴结转移这五个因素之间无统计学意义(P＞0.05)。④livin蛋白表达和caspase-3蛋白表达情况用Spearman进行统计学分析，发现在喉鳞癌组织中Livin表达和Caspase-3表达呈负相关关系。
结论①livin在LSCC组织中高表达，且其表达与喉鳞状细胞癌的临床分期、病理分型相关。提示Livin蛋白的表达可能参与了喉鳞状细胞癌的发生、发展过程。②caspase-3在LSCC组织中低表达，提示Caspase-3蛋白的表达可能参与了喉鳞状细胞癌的发生过程。③livin表达与Caspases表达在喉鳞状细胞癌中呈负相关关系，提示caspase-3可能受livin抑制调节，二者共同参与了喉鳞状细胞癌的发病机制。
Objective To detect the expression of Livin and cysteine asp-artate-specific proteases-3(Caspase-3) protein in laryngeal squamous cellcarcinoma, and their correlation.
Methods To Select43cases of laryngeal squamous cell carcinomaconfirmed by preoperative biopsy and HE staining pathology or ganizations(for the first time admitted patients, not the anti-tumor treatment ofradiotherapy and chemotherapy and immunosuppressive drugs),and at the sametime to select43cases of laryngeal mucosa tissue of patients with OSAHS as acontrol group. And immunohistochemical assay were performed to detect theLivin protein and Caspase-3protein expression in laryngeal squamous cellcarcinoma and control group in the situation.Then the laboratory data wereanalyzed of the correlation between the two gene. We used the SPSS16.0asStatistic analysis software and were statistically analyzed using Chi-squaretest，Fisher’s exat test and Spearman correlation analysis, take a=0.05for theinspection level, P <0.05was considered statistically significant, P <0.01asstatistically significant difference.
Results①The Livin expression positive rate was74.42%in Laryngealsquamous cell carcinoma and41.86%positive rate of Caspase-3.As comparedwith control group laryngeal mucosa difference was statistically significant(P<0.05).②The Livin protein expression was related to clinicalstage,pathological differentiation of laryngeal squamous cell carcinoma (P <005). But between patient age, gender, lymphoid metastasis these factors wasnot significant (P>0.05)；③The Caspase-3protein expression was no related topatient age, gender, clinical stage, pathology differentiation degree and lymphoid metastasis these five factors were not significant (P>0.05).④TheSpeannan rank correlation analysis method was used to analyze the correlationof Livin and Caspase.It showed that the expression of Livin was negativerelated to that of Caspase-3in Laryngeal squamous cell carcinoma.
Conclusion①The expression of Livin was significantly high inLaryngeal squamous cell carcinoma.And it expression was related to clinicalstage,pathological differentiation of laryngeal squamous cell carcinoma. Thehigh expression of Livin may indicate that it involved in the occurrence anddevelopment of laryngeal squamous cell carcinoma.②Caspases-3with lowexpression in LSCC suggest that it may be involved in the process of Laryngealsquamous cell carcinoma.③The expressions of Livin and Caspases-3inlaryngeal squamous cell carcinoma showed negative correlation. This showedthat caspase-3activation may be affected by the Livin protein regulation,bothinvolved in the pathogenesis of laryngeal squamous cell carcinoma.
引文
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[13]Crnkovic-MertensI，Semzow J Hoppe-Seyler F,etaL Isoform-specificsilencing of the Livin gene by RNA interference defines Livin beta as keymediator inhibitor in Hela cells.J MolMed，2006，84(3):232一240
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[2] Hauser HP，Bardroff M，Pyrowolakis G，et al．A giant ubiquitin-conjugatingenzyme related to IAP apoptosis inhibitors[J].Cell Biol，1998，141：1415-1422．
[3] Liu B，Han M，Wen JK，et al． Livin/ML-IAP as a new target for cancertreatment [J].Cancer Lett，2007，250(2):168-176．
[4] Gazzaniga P，Gradilone A，Giuliani L，et al．Expression and prognosticsignificance of LIVIN，SURVIVIN and other apoptosis related genes in theprogression of superficialbladder cancer[J]．Ann Oncol，2003，14：85-90．
[5] Yagihashi A，Asanuma K，Tsuji N，et al．Detection of antilivin antibodyin gastrointestinal cancer patients[J]．Clin Chem，2003，49：1206-1208．
[6] Crnkovic-Mertens I，Hoppe-Seyler F，Butz K．Induction of apoptosis intumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAPgene[J]．Oncogene，2003，22：8830-8836．
[7] Sanna MG，da Silva Correia J，Ducrey O，et al．IAP suppression ofapoptosis involves distinct mechanisms：theTAK1/JNK1signaling cascadeand caspase inhibition[J]．Mol CellBiol，2002，22：1754-1766．
[8] Crook NE，C1em RJ，Miller LK．An apoptosis-inhibiting baculovirus genewith a zinc finger-like motif [J].Virol,1993,67（4）:2168-2174.
[9] Deveraux QL，Reed JC．IAP family proteins-suppressors of apoptosis [J].Genes Dev，1999，13(3)：239-252.
[10]Nachmias B，Ashhab Y，Ben-Yehuda D.The inhibitor of apoptosis proteinfamily (IAPs)：an emerging therapeutic target in cancer [J].Semin CancerBiol，2004，1（4）：231-243.
[11]Salvesen GS，Duckett CS．IAP proteins: blocking the road to death’sdoor[J].Nat RevMol Cell Biol，2002,3(6):401-410．
[12]Joazeiro CA,Weissman AM.RING finger proteins:mediators of ubiquitinligase activity [J]．Cell，2000，102（5）：549-552
[13]Roy N，Deveraux QL，Takashashi Ret al．The c-IAP-1and c-IAP-2pro-teins are direct inhibitors of specific caspases [J]．EMBOJ，1997，16（23）：6914-6925
[14]Holcik M，Gibson H，Korneluk RG．XIAP：apoptotic brake and promisingtherapeutic target[J]．Apoptosis，2001，6：253-261.
[15]Chang H, Schimmer AD.Livin/melanoma inhibitor of apoptosis protein asa potential therapeutic target for the treatment of malignancy[J]. MolCancer Ther,20076:24–30.
[16]Ma L, Huang Y, Song Z.Livin promotes Smac/DIABLO degradation byubiquitin–proteasome pathway. Cell Death Differ1,2006,3:2079–2088Kasof GM, Gomes BC.Livin, a novel inhibitor of apoptosis protein familymember. J Bio Chem,2006,276:3238–3246
[17]Franklin MC, Kadkhodayan S, AckerlyHet al. Structure and functionanalysis of peptide antagonists of melanoma inhibitor of apoptosis(ML-IAP)[J]. Biochemistry,2003,42(27):8223–8231.
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