凋亡抑制新基因Livin与宫颈癌的关系

凋亡蛋白抑制因子(IAP)是一类抑制凋亡的调节分子,其成员Livin是新发现的凋亡抑制基因,能够与内源IAP抑制剂SMAC和caspase-3、caspase-7、caspase-9结合,发挥抗细胞凋亡的作用.近年来,研究发现Livin在宫颈癌细胞及组织中高表达,而且通过检测癌细胞凋亡有助于确定宫颈癌的发生机制及其疗效评价,因此研究Livin结构与功能及作用机制对于宫颈癌的发生、发展、诊断与治疗有积极意义.     

凋亡抑制蛋白Livin:抗癌新靶点

Livin,又称ML-IAP或KIAP是与肿瘤发生发展密切相关的凋亡抑制蛋白家族( inhibitor of apoposis proteins, IAPs)中的新成员,能够与内源IAP抑制剂SMAC 和 caspase-3,caspase-7,caspase-9结合,发挥抗细胞凋亡的作用.它特异性高表达于肿瘤组织而使肿瘤组织对放化疗作用变得耐受.近来,体内外研究表明下调或抑制Livin基因表达增加了肿瘤细胞凋亡率,抑制肿瘤细胞的增殖和集落形成能力,提高肿瘤细胞对化疗药物和放疗的敏感性.Livin 将成为肿瘤治疗的潜在靶点.     

Livin与消化道肿瘤

凋亡蛋白抑制因子（inhibitor of apoptosis protein,IAP）是一类抑制凋亡的调节分子,其成员Livin是新发现的凋亡抑制基因,通过与内源IAP抑制剂SMAC和Caspase－3,Caspase－7,Caspase－9结合,发挥抗细胞凋亡的作用。与多种肿瘤的发生密切相关。我们就其分子结构、生物学特征、抗细胞凋亡作用机制以及与消化系统肿瘤的关系等研究现状作一介绍。     

凋亡抑制蛋白Livin在食管癌中的研究进展

Livin是新近发现的人类IAP家族成员,为类内源性细胞凋亡抑制蛋白,Livin在多种肿瘤细胞中高表达,通过抑制caspase在许多物种中起着抑制细胞凋亡的作用.近年来人们发现Livin特异性表达于食管癌细胞中,通过下调或抑制Livin基因的表达及诱导产生特异性地识别Livin的抗体可抑制、杀死肿瘤细胞,为食管癌的诊断、细胞和基因靶向治疗等提供新的方法.     

凋亡抑制蛋白Livin与肿瘤

近年发现的凋亡蛋白抑制因子(inhibitor of apopto-sis protein,IAP)是一类重要的抗细胞凋亡因子与肿瘤的发生发展关系密切,目前人类IAP家族已发现NIAP、XIAP、cIAP1c、IAP2、Survivin、apollonI、LP2和Livin共8个成员[1],其抗凋亡功能远强于Bcl-2家族[2],在肿瘤的发病机制中起着重要作用,Livin是新近发现的一个IAP家族成员,因其特异性高表达于肿瘤组织,故己成为当今研究的热点[3]。1 Livin的结构和组织分布Livin是IAPs家族中的最新成员,于2000年是由4个不同的实验小组几乎在同一时期所发现,均采用IAP同源序列(BIR或RING)…     

凋亡抑制蛋白Livin与肿瘤

凋亡抑制蛋白(IAP)家族是一类重要的抗凋亡因子,与肿瘤的发生、发展密切相关.Livin选择性表达于多种常见的恶性肿瘤中,提示该基因可能在肿瘤形成过程中起重要作用.研究其生物学特性与功能及作用机制对于肿瘤的发生、发展、细胞耐药、肿瘤的治疗、预后等有重大意义.近年来对于以livin为靶点的基因与免疫治疗也成为热点研究之一,为肿瘤的综合治疗提供了新的策略和方向.     

Livin蛋白和血管内皮生长因子在肿瘤中的表达

Livin是抑制凋亡蛋白家族（IAP）的新成员,在多数恶性肿瘤组织中高表达,其主要功能是抑制细胞凋亡。细胞凋亡与肿瘤细胞的发生、发展密切相关,肿瘤的生存更有赖于血管的生成。血管内皮生长因子（VEGF）是目前所知作用最强的一种促血管生长因子,几乎在所有的人体肿瘤和肿瘤细胞株中皆有表达。现就Livin和VEGF在肿瘤中的表达作一综述。     

Livin与肿瘤细胞凋亡的研究现状

凋亡蛋白抑制因子(inhibitor of apoptosisprotein,IAP)是一类抑制凋亡的调节分子,其成员livin是新发现的凋亡抑制基因,存在同基因不同剪切的两个异构体:Livinα和Livinβ;livin在多数肿瘤组织中高表达;其作用机制主要通过:1)抑制半胱天冬酶3/7/9(caspase3/7/9)的活性;2)激活TAK1/JNK1信号转导途径,同过非C途径抑制TNF及ICE诱导的细胞凋亡,来阻断细胞凋亡过程。livin与肿瘤发生有密切关系,并可能作为诱导肿瘤凋亡治疗的新靶点     

Apollon凋亡抑制蛋白与肿瘤治疗的研究进展

凋亡抑制蛋白(inhibitor of apoptosisprotein,IAP)家族是在病毒、真核生物、哺乳动物等多个物种中广泛存在的进化高度保守的一类抗细胞凋亡调节因子,目前共发现IAP家族中有XIAP、c-IAP1、c-IAP2、NAIP、Apollon、Livin、Survivin、ILP-2等8个成员,其中Apollon、Livin、Survivin、XIAP是其中的主要成员,抑制细胞凋亡作用较强[1].Apollon在人体多种恶性肿瘤中高表达.本文就Apollon基因生物特性、组织表达及功能以及其在肿瘤治疗中的应用等研究进展进行综述.     

Livin异构体基因沉默对肺腺癌SPC-A1 细胞化疗增敏效应研究

背景与目的 前期研究发现,凋亡抑制蛋白家族(IAP)新成员Livin尤其是Livinα,参与肺癌的发生发展,是肺癌细胞化疗耐药的重要机制之一.本研究的目的是利用基因转染和RNA干涉(RNAi)技术,在肺腺癌SPC-A1细胞中建立Livin异构体α和β特异的基因沉默体系,探讨其对增加SPC-A1细胞化疗敏感性的不同作用及价值.方法 在SPC-A1细胞中稳定表达Livinα β、Livinα和Livinβ特异性小干涉RNA(siRNA),体外实验用甲基偶氮唑蓝(MTT)法,研究Livin基因沉默后SPC-A1细胞对化疗药物的敏感性改变;体内实验利用荷瘤裸鼠模型,研究Livin基因沉默后荷瘤小鼠对顺铂的敏感性改变.结果 Livinα β、Livinα和Livinβ基因沉默后,SPC-A1细胞对顺铂、卡铂、环磷酰胺、阿霉素等多种化疗药物敏感性增加(P＜0.05),其中,Livinα β基因沉默能更有效增加肺癌细胞化疗敏感性(P＜0.01).动物实验表明,pSilencer-Livinα β组、pSilencer-Livinα组和pSilencer-Livinβ组抑瘤率分别为146.1%、130.7%、110.5%.结论 Livin异构体尤其是Livinα β可作为肺癌细胞化疗增敏的分子靶点,其基因沉默有望成为非小细胞肺癌基因治疗新手段.     

Antisense oligonucleotide targeting Livin induces apoptosis of human bladder cancer cell via a mechanism involving caspase 3

Background and Aim

in recent years, Livin, a new member of IAPs family, is found to be a key molecule in cancers. Researchers consider Livin may become a new target for tumor therapy; however, the role of it in bladder cancer is still unclear. The purpose of this article is to investigate Antisense Oligonucleotide (ASODN) of Livin on treating bladder cancer cell and underlying mechanisms.

Methods

Phosphorathioate modifying was used to synthesize antisense oligonucleotides targeting Livin, followed by transfection into human bladder cancer cell 5637. After transfection, Livin mRNA and protein level, cell proliferation and apoptosis changes, caspase3 level and its effect on human bladder cancer transplantable tumor in nude mice were measured.

Result

results showed Livin ASODN effectively inhibited Livin expression and tumor cell proliferation, and these effects probably through enhanced caspase3 activity and apoptosis of tumor cells. In nude mice transplantable tumor model, Livin expressions were inhibited meanwhile caspase3 expression was increased. Tumor growth slowed down and apoptosis was enhanced.

Conclusion

Our data suggest that Livin plays an important role in inhibiting apoptosis of bladder cancer cells. Livin ASODN may promote cell apoptosis, inhibit bladder cancer growth, and become one of the methods of gene therapy for bladder cancer.     

凋亡抑制蛋白Livin在肿瘤治疗中的新进展

Livin是凋亡抑制蛋白的一个新成员,可以编码抑制凋亡的负性调节蛋白。Livin在大多数肿瘤中高表达,体内外研究发现其表达降低可以增加肿瘤细胞凋亡,降低肿瘤细胞的生长潜能,增加肿瘤细胞对化疗的敏感性。因此,Livin可以作为肿瘤治疗的新的靶点。     

Livin与肿瘤细胞凋亡的研究现状

凋亡蛋白抑制因子（inhibitor of apoptosis protein，IAP）是一类抑制凋亡的调节分子，其成员livin是新发现的凋亡抑制基因，存在同基因不同剪切的两个异构体：Livina和Livinβ；livin在多数肿瘤组织中高表达；其作用机制主要通过：1）抑制半胱天冬酶3／7／9（caspase3／7／9）的活性；2）激活TAK1／JNK1信号转导途径，同过非C途径抑制TNF及ICE诱导的细胞凋亡，来阻断细胞凋亡过程。livin与肿瘤发生有密切关系，并可能作为诱导肿瘤凋亡治疗的新靶点     

Rapid induction of mitochondrial events and caspase-independent apoptosis in Survivin-targeted melanoma cells

The inhibitor of apoptosis (IAP) protein Survivin is expressed in most cancers and is a key factor in maintaining apoptosis resistance. Although several IAPs have been shown to act as direct inhibitors of caspases, the precise antiapoptotic function of Survivin remains controversial. To clarify the mechanism by which Survivin protects cells, we investigated the kinetics of apoptosis and apoptotic events following Survivin inhibition utilizing a melanoma cell line harboring a tetracycline-regulated Survivin dominant-negative mutant (Survivin-T34A). Blocking Survivin resulted in both caspase activation and apoptosis; however, the level of apoptosis was only partially reduced by caspase inhibition. Survivin blockade also resulted in mitochondrial events that preceded caspase activation, including depolarization and release of cytochrome c and Smac/DIABLO. Levels of other IAPs were not altered in Survivin-targeted cells, although modest cleavage of XIAP and Livin was observed. The earliest proapoptotic event observed in Survivin-targeted cells was nuclear translocation of mitochondrial apoptosis-inducing factor (AIF), known to trigger both apoptotic mitochondrial events and caspase-independent DNA fragmentation. These findings suggest that a key antiapoptotic function of Survivin relates to inhibition of mitochondrial and AIF-dependent apoptotic pathways, and its expression in melanoma and other cancers likely protects against both caspase-independent and -dependent apoptosis.     

Livin/ML-IAP as a new target for cancer treatment

Livin is a member of the inhibitors of apoptosis protein (IAP) gene family, which encodes negative regulatory proteins that prevent cell apoptosis. Livin is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to chemotherapeutic agents. Several studies in vitro and in vivo have demonstrated that down-regulation of Livin expression increases the apoptotic rate, reduces tumor growth potential and sensitized tumor cells to chemotherapeutic drugs. This review will focus on the role of this protein during cancer development and progression and will demonstrate possible targets for cancer therapy.     

Livin在肺癌中的表达及与pro-caspase3的相关性分析初步探讨

背景与目的Livin是凋亡抑制蛋白新成员之一,目前研究表明Livin在各种恶性肿瘤(包括肺癌)中过度表达,并促进肿瘤发生发展。本研究目的在于探讨在蛋白水平凋亡抑制蛋白livin在肺癌组织中的表达及与肺癌组织类型、术前化疗、淋巴结转移的关系;探索livin蛋白表达与pro-caspase3蛋白的关系。方法采用Western-blot方法检测肺癌组织及对照组中livin及pro-caspase3的蛋白水平的表达。结果27例肺癌组织中livin蛋白表达阳性率为55.6%(15/27),明显高于对照组癌旁组织(20.0%)和良性疾病肺组织(16.7%)(P<0.01)。其中在肺腺癌、鳞癌(包括大细胞癌)组织中livin蛋白阳性率分别为76.92%,38.46%,1例小细胞癌阴性;livin蛋白在术前有无化疗肺癌组织中及淋巴结有无转移组织中表达无明显差异(P>0.05)。应用凝胶成像仪测量各指标灰度值后显示,肺癌组织livin蛋白表达明显高于对照组(P<0.05);pro-caspase3蛋白在肺癌组织中表达高于对照组(P<0.01),livin蛋白表达与pro-caspase3蛋白表达呈正相关趋向。结论Livin蛋白可在不同病理类型肺癌组织中不同程度表达,livin蛋白表达与术前化疗及淋巴结转移无明显相关;livin蛋白表达与pro-caspase3蛋白呈正相关趋势,可能与其与pro-caspase3蛋白结合抑制其加工活化有关。     

Caspase-mediated cleavage converts Livin from an antiapoptotic to a proapoptotic factor: implications for drug-resistant melanoma

Inhibitor of apoptosis protein (IAP) is a family of intracellular proteins that plays an essential role in the regulation of apoptosis. Recently, we and others discovered a new member of this family, termed Livin. Many studies have focused on the inhibitory effect of IAPs on caspases. Here, we describe a novel regulatory mechanism by which Livin is cleaved by the caspases. Strikingly, the cleaved Livin, although containing intact baculovirus IAP repeat and RING domains, does not only lose its antiapoptotic function but also gains a proapoptotic effect. The cleavage is site specific at Asp-52 and is restricted to effector caspase-3 and -7. Most importantly, we demonstrate the role of Livin and this regulatory mechanism in the drug resistance of melanoma patients. Using primary cultures derived from melanoma patients, we found a correlation between Livin overexpression, in vitro drug resistance, and the patient's clinical response.