Survivin与肿瘤研究进展

Survivin作为凋亡抑制蛋白家族(IAPs)的一个新成员，以细胞周期依赖性的方式调节表达，在纺锤体检查点与有丝分裂装置结合而调节G2／M分裂进程；通过BIR结构域抑制细胞凋亡，与其它IAPs比较具有更强的选择性。目前关于它在亚细胞池中的定位与功能仍存在争论：有研究表明，survivrin定位在纺锤体上，直接锚于死亡蛋白酶一9并抑制其活性，正因为它具有细胞周期依赖性表达又具有抗凋亡的双重特性，有人提出survivin是有丝分裂缺陷细胞的“死亡开关”；另外一些研究表明，survivin定位在着丝粒的动粒、细胞裂解沟和中间体上，认为它实际是染色体乘客蛋白之一，可致胞质分裂缺陷，而不是抑制凋亡。然而在细胞癌变进程中，survivrin的表达与凋亡成负相关，而与肿瘤细胞增殖和血管生成成正相关；人类肿瘤中，survivin的表达水平升高与生存时间缩短和不良预后关系密切；survivin主要位于胞质池中并常显示预后不良，但核池水平高却预后良好。survivin存在三种剪切体，SUVvivin-δEx3、survivin-2B和δ-3B，现在认为它们可能具有不同的时空表达模式，通过多信号通路作用在有丝分裂进程和抗凋亡的界面，是保护分裂细胞存续能力的必须分子；靶向survivin技术能够诱导细胞凋亡，抑制肿瘤生长，提高肿瘤细胞对放化疗的敏感性，这些都预示着survivin可能成为一个肿瘤诊断和治疗上的潜在靶点。     

存活蛋白在子宫内膜癌中的表达及其在细胞凋亡中的作用

目的:探讨子宫内膜癌中存活蛋白(survivin)的表达及其对细胞凋亡的作用.方法:免疫组织化学法检测survivin在子宫内膜癌组织中的表达,并且应用RNA干扰技术沉默survivin基因,RT-PCR和Western印迹法检测RNA干扰效果,FCM法检测RNA干扰前后细胞凋亡的变化,Western印迹法检测凋亡相关蛋白caspase-3、caspase-8和bcl-2的表达变化.结果:子宫内膜癌组织中survivin蛋白的阳性率显著高于不典型增生和正常内膜组织(P<0.05和P<0.01).RNA干扰有效抑制了survivin mRNA和蛋白的表达(均为P<0.01),并且诱导了细胞凋亡,2个干扰组的细胞凋亡率均显著高于对照组(P<0.01).RNA干扰亦上调了活性caspase-3、caspase-8的表达.结论:survivin基因的异常表达与子宫内膜癌的发生密切相关,抑制其表达可以诱导子宫内膜癌细胞发生凋亡.     

Bcl-2在肝癌和胰腺癌中的表达及意义

Bcl-2（B-celllymphoma／leukemia-2）基因是Bcl-2基因家族的一个重要成员，该基因是Tsujimoto等从B滤泡性淋巴瘤染色体断裂点发现的凋亡抑制基因，Bcl-2作为一种重要的凋亡调控基因，他不仅能够抑制细胞凋亡，延长细胞寿命，而且参与细胞增生的调控，他可以调控细胞由G0期向S期转换的时间，其过表达可以延长静止细胞的细胞周期进程，但不影响细胞的生长。据研究显示，Bcl-2的磷酸化亦能影响细胞周期进程，此外，Bcl-2在肿瘤的形成及肿瘤多药耐药的形成中也起着重要的作用，Bcl-2基因作为重要的凋亡抑制基因在多种肿瘤中得到研究。现综述其在肝癌及胰腺癌中的表达及意义。     

ING1基因与肿瘤关系的研究进展

肿瘤的发生是一个多基因参与的多步骤的复杂过程，肿瘤抑制基因可能是抑制肿瘤发生的重要保护机制。ING1是1996年发现的一个候选抑癌基因，定位于人染色体13q33～34。ING1mRNA有ING1a、ING1b和ING1c三种变位剪接形式，分别编码三种不同的蛋白质：p47^ING1a．p33^ING1b和p24^ING1c，其中p33^ING1b是目前肿瘤研究的热点。ING1蛋白在正常细胞主要位于细胞核内，部分肿瘤细胞则在细胞质表达较多。ING1具有调控细胞周期、诱导细胞凋亡和DNA损伤修复的作用。其中，p33^ING1通过调控细胞周期负向调节细胞生长而p47^ING1a过表达则对细胞生长无明显影响。p33^ING1b过量表达可以促进p21^WAF1表达，协同p53引起细胞周期阻滞从而抑制肿瘤细胞生长。ING1基因可能是通过乙酰化依赖通路的活性调节来改变基因的表达，参与多种过程的调控。ING1编码的蛋白通过组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（HDACs）参与染色质的重塑，在DNA损伤修复方面发挥重要作用。ING1基因与脑瘤、肝癌和胃癌等多种肿瘤的发生发展有关。ING1基因的结构特点、生物学功能与肿瘤的发生发展密切相关。     

生存素与血液肿瘤的研究进展

Survivin(生存素)基因是近年来发现的一种新的抗凋亡因子,属凋亡蛋白抑制因子(inhibitorapoptosisprotein,IAP)家族,具有抑制细胞凋亡作用并在细胞的有丝分裂过程中起重要的作用。Survivin广泛表达于人类恶性肿瘤组织,其表达与肿瘤预后不良及肿瘤化疗耐药密切相关。其在多种血液肿瘤中均有表达。本文就survivin的分子结构、组织分布、作用机理、在血液肿瘤中的表达及其在肿瘤中的治疗进行综述。     

survivin和PTEN在胃癌中的研究进展

肿瘤的发生与细胞增殖、凋亡和基因变异、缺失有关.survivin是一个具有调节细胞有丝分裂和抑制细胞凋亡双重功能的凋亡抑制蛋白.PTEN是-个具有双重特异性磷酸酶活性的抑癌基因,其主要功能是参与调控细胞增殖、迁移和凋亡的过程.研究显示survivin的过表达和PTEN的失活均与肿瘤的发生、发展有关.本文就survivin和PTEN的分子结构、作用机制及其在胃癌中的应用研究进行综述.     

survivin和livin与肿瘤细胞凋亡

细胞凋亡的过程通过多种信号转导实现,并由许多凋亡相关基因调节控制。凋亡蛋白抑制因子(IAP)与肿瘤细胞的无限增殖关系密切。新近发现的IAP包括survivin、livin与肿瘤密切相关,其抗凋亡机制有待进一步研究。     

Livin抗凋亡机制与肿瘤

细胞凋亡是由多种因子介导的细胞主动死亡的过程，对机体或组织维持内环境的稳定和生物体的生长发育、生命周期、衰老死亡都有着重要的作用。凋亡抑制也是肿瘤发生的重要机制，凋亡通路的紊乱、促进凋亡因子的抑制、凋亡因子的过表达以及凋亡基因的表达失控都会导致肿瘤的发生和发展。而且，凋亡紊乱还会导致肿瘤对化疗的抵抗。     

XIAP与肿瘤化疗耐药关系的研究进展

研究发现，造成肿瘤对化疗药物耐药的重要原因是化疗药物介导的细胞凋亡指数的下降。凋亡抑制蛋白在抑制细胞凋亡中起非常重要的作用，而X连锁的凋亡抑制蛋白(XIAP)是凋亡抑制蛋白家族中作用最强的一种，并且在多种肿瘤组织和细胞中高表达。已有研究证明，其在肿瘤对化疗产生耐药的机制中起重要作用。     

survivin基因与肿瘤放化疗的敏感性及相关基因治疗

研究显示调亡抑制蛋白survivin与肿瘤放化疗抵抗密切相关,可通过对survivin基因的修饰,抑制survivin基因的表达,使其丧失凋亡抑制功能,从而增加肿瘤的自发性凋亡及放化疗诱发的凋亡,抑制肿瘤生长,提高肿瘤对放化疗的敏感性.     

Implication of alternative splice transcripts of caspase-3 and survivin in chemoresistance

Recent studies have shown that resistance to apoptosis may contribute to chemoresistance. Alteration of caspases, such as caspase-3, results on decreased apoptosis. Genes of IAP (inhibitor of apoptosis proteins) family, such as survivin, were also implicated in tumor development where they are mutated or have deregulated expression. Initial studies revealed strong survivin expression in several fetal tissues and some proliferating adult tissues, whereas no survivin expression was detected in a range of adult tissues. Although the factors at the origins on survivin re-expression in tumors are still unknown, the anti-apoptotic function of survivin is mediated in part by inhibiting caspase-3 activity. Recently, functionally divergent splice variants resulting from alternative splicing, with apoptotic (for caspase-3) or anti-apoptotic (for survivin) opposite activities have been described. The alternative splice variant, caspase-3s results from exon 6 deletion and shows antagonist of apoptotic property of caspase-3. Three alternative splice variants of survivin (survivin-DeltaEx3, survivin-2B and survivin-3B) differing in their anti-apoptotic properties were reported. While the anti-apoptotic effect of survivin-DeltaEx3 is preserved, survivin-2B has lost its anti-apoptotic potential and may act as a naturally occurring antagonist of survivin and survivin-DeltaEx3. At present, little is known about properties of survivin-3B. Several evidences indicate that in several cancers, the ratio of splice variants is significantly altered, and modifications of splicing pathways have been developed for cancer treatment. Recent investigations have shown that expression of alternative splice variants of caspase-3 and of survivin were also altered in many human cancers, and that variations in their expression were associated with tumor progression and chemoresistance. In this article, we describe recent data concerning alternative splice variants of these two proteins.     

Survivin splice variants regulate the balance between proliferation and cell death

Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-DeltaEx3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.     

Association of p53 gene alterations with the expression of antiapoptotic survivin splice variants in breast cancer

Survivin, a member of the inhibitory apoptosis protein family, gives rise, by an alternative splicing, to four variants with different functions. Many experimental studies indicate that p53 can regulate the expression of survivin and some of its splice variants. Although both the expression of survivin splice variants and the p53 gene were frequently altered in human cancers, nothing is known about their interactions in in vivo tumour samples. Here, we report that, in 162 breast carcinomas, p53 mutations are significantly associated with an increased expression of survivin and, in particular, its antiapoptotic splice variants (survivin-DeltaEx3 and survivin-3B). The upregulation of these variant expressions is particularly related to p53 mutations occurring in the residues belonging to the tetramerization domain. The loss of heterozygosity in the p53 gene is also associated with an increased expression of the survivin-DeltaEx3 variant. The expression of the proapoptotic variants (survivin-2B and survivin-2alpha) is not affected by any of these alterations. Our results provide for the first time in vivo evidence that, in human breast cancer, the survivin expression as well as its splicing depends on the p53 status. The results also suggest that the upregulation of antiapoptotic survivin variant expression by the mutant p53 may increase breast cancer cells survival and resistance to therapy.     

Survivin deficiency induces apoptosis and cell cycle arrest in HepG2 hepatocellular carcinoma cells

The postulated dual roles of survivin as an anti-apoptotic factor and a mitotic inducer have placed this factor in the spotlight of cancer research. The purpose of this study was to investigate whether survivin might connect the cell cycle with apoptosis. Here, by simultaneously monitoring survivin deficiency-induced morphological changes of HepG2 cells using time-lapse imaging as well as determining apoptosis progression, we observed synchronized defective mitosis characterized by multinucleated and polyploid cells and cell cycle arrest at S phase or G2/M phase followed by apoptosis, the processes of which depended on the simultaneous destruction of specialized subcellular compartments of survivin and activation of caspase-3-like protease. These findings showed that the survivin protein acted as mitotic regulator and apoptosis inhibitor, but may also possess the role of a bridge in integrating apoptosis and cell division. An essential prerequisite of this pathway was the specialized subcellular localization of survivin. The overexpression of survivin was required to maintain cell viability and proper cell cycle transitions, and to preserve genetic fidelity during cell division in HepG2 cells.     

Nuclear and cytoplasmic survivin: molecular mechanism, prognostic, and therapeutic potential

Survivin's proposed dual role as an apoptosis inhibitor and a mitotic effector positioned it in the front line of cancer research. Notably, survivin is detected as a cytoplasmic and nuclear protein in cancer patients, which stimulated numerous studies to investigate and to speculate on the functional and prognostic significance of its dynamic localization. Recent evidence shows that the direct interaction of survivin with the nuclear export receptor Crm1 is critically involved in its intracellular localization and cancer-relevant functions. Here, we review our current understanding of the Crm1/survivin interface and discuss its potential prognostic and therapeutic relevance.