XIAP及survivin 在原发性肝细胞癌组织中的表达及其相关性研究

目的：探讨X 连锁凋亡抑制蛋白（XIAP）和survivin 在原发性肝细胞癌中的表达及两者的相关性。方法：选取本院收治的60例原发性肝细胞癌患者,应用免疫组织化学染色的方法对肝癌组织及癌旁组织中的XIAP及survivin 的表达进行检测。结果：经比较,肝癌组织中XAIP 及survivin 的阳性率均显著高于癌旁组织,差异有统计学意义。XIAP 和survivin 的表达强度与肿瘤的大小无关,但随肿瘤的分化程度的降低而升高,且不同分化程度之间差异有统计学意义;XIAP 和survivin 存在正相关关系。结论：XIAP与Survivin 在肿瘤组织中的高表达在促进肿瘤发生、增殖、转移以及耐药,并且能够降低肿瘤的分化程度,增加肝癌的恶性程度。此外,两者可能存在协同作用,但两者的相关性及作用机制仍需进一步探讨。     

XIAP及survivin在原发性肝细胞癌组织中的表达及其相关性研究

目的：探讨X连锁凋亡抑制蛋白（XIAP）和survivin在原发性肝细胞癌中的表达及两者的相关性。方法：选取本院收治的60例原发性肝细胞癌患者,应用免疫组织化学染色的方法对肝癌组织及癌旁组织中的XIAP及survivin的表达进行检测。结果：经比较,肝癌组织中XAIP及survivin的阳性率均显著高于癌旁组织,差异有统计学意义。XIAP和survivin的表达强度与肿瘤的大小无关,但随肿瘤的分化程度的降低而升高,且不同分化程度之间差异有统计学意义;XIAP和survivin存在正相关关系。结论：XIAP与Survivin在肿瘤组织中的高表达在促进肿瘤发生、增殖、转移以及耐药,并且能够降低肿瘤的分化程度,增加肝癌的恶性程度。此外,两者可能存在协同作用,但两者的相关性及作用机制仍需进一步探讨。     

心脏特异性高度表达的抗凋亡蛋白——ARC

与凋亡(apoptosis)相关的许多心脏疾病如心肌梗死、心肌病及心衰等严重威胁着人类的健康和生命.寻找有效手段防治这些心脏病是当前医学研究的热点.ARC(带有caspase富集功能域的凋亡抑制因子)是新近发现的唯一在心脏大量且特异表达的抗凋亡蛋白,其全称是带有caspase富集功能域的凋亡抑制因子.ARC可被持续性磷酸化并参与阻断凋亡发生途径的多个层面.因此,ARC是一种强大的抗心肌凋亡蛋白.     

一种抗凋亡蛋白——存活素的研究

存活素(survivin)是一种新近发现的16．5kD细胞内蛋白,属于抗细胞凋亡蛋白家族。在胚胎和各类肿瘤中均表达,但在除胸腺和睾丸以外的成人组织中未被发现。阐明survivin在细胞凋亡和增生中的分子机制及其作用,在抗癌治疗和抑制对机体有害的细胞凋亡方面具有重要意义。     

抗内毒素治疗的新策略

脂多糖(Lipopolysaccharide,LPS)是G-菌造成的败血症或脓毒性休克病理中最重要的致病因素,若在整个病理过程的上游,即在细菌内毒素水平阻断脓毒性休克的发生,就可能限制或阻止病理性的次级炎症级联反应。本文综述了各种不同来源的LPS结合蛋白在结合LPS从而中和并阻断内毒素的过程中的功效及应用现状,探讨了最终用于人类败血症或脓毒性休克临床治疗的有效方案。     

癌变组织特异高表达抗凋亡蛋白——ARC

带有caspase富集功能域的凋亡抑制因子（ apoptosis repressor with a caspase recuitment domain, ARC ）是新近发现的重要抗凋亡蛋白。在正常组织中,ARC高度特异地表达在终末分化组织如心肌、骨骼肌和大脑,而在非终末分化组织不表达或微量表达。但是,当非终末分化组织发生癌变时表达大量的ARC。ARC过表达可以抑制阿霉素或射线诱导的癌细胞死亡,提示ARC在癌细胞中具有抗趋化或抗放射线损伤的作用。因此,ARC可能成为一种新的肿瘤标记物,也可能是决定肿瘤对各种治疗方法反应性的一个重要因素。     

Bcl—2家族蛋白与细胞凋亡

Bcl 2家族蛋白是在细胞凋亡过程中起关键性作用的一类蛋白质。在线粒体上 ,Bcl 2家族蛋白通过与其他凋亡蛋白的协同作用 ,调控线粒体结构与功能的稳定性 ,发挥着细胞凋亡“主开关”的作用。Bcl 2家族包括两类蛋白质 :一类是抗凋亡蛋白 ,另一类是促凋亡蛋白。在细胞凋亡时 ,Bcl 2家族中的促凋亡蛋白成员发生蛋白质的加工修饰 ,易位到线粒体的外膜上 ,引起细胞色素c、凋亡诱导因子等其他促凋亡因子的释放 ,导致细胞凋亡 ;而平时被隔离在线粒体等细胞器内的该家族的抗凋亡蛋白成员则抑制细胞色素c和凋亡诱导因子等促凋亡因子的释放 ,具有抑制细胞凋亡的功能。但一旦这类抗凋亡蛋白成员与激活的促凋亡蛋白发生相互作用后 ,便丧失了对细胞凋亡的抑制作用 ,造成线粒体等细胞器的功能丧失和细胞器内促凋亡因子的释放 ,导致细胞凋亡。现以Bcl 2家族调控细胞凋亡的最新研究进展为基础 ,对Bcl 2家族成员及其蛋白质结构、分布和调控细胞凋亡的分子机制进行综述。     

Akt抗凋亡机制与癌症治疗

细胞凋亡与抗凋亡的调节异常与许多疾病特别是癌症的发生、发展相关。PI-3K／Akt信号转导通路在抗凋亡机制中发挥了重要作用。蛋白激酶B(Akt)是一种丝氨酸／苏氨酸蛋白激酶,当Akt磷酸化下游靶点后,可阻碍细胞凋亡。最近,Akt抗凋亡机制的研究取得了极大的进展。随着研究的不断深入,尤其是更多Akt底物及抑制剂的不断发现,必将对多种癌症的治疗及药物筛选产生积极的影响。     

抗凋亡因子Survivin研究进展

Survivin是在肿瘤组织及胚胎中发现的一类细胞因子,它是IAPs(inhibitorsofapoptosisprotein)家族的成员之一,具有其独特的分子结构和组织表达特异性,在细胞中参与细胞周期的调控,主要在细胞周期的G2/M期通过抑制caspase-3及caspase-7的活性发挥作用.Survivin在细胞中的活性可能受p53的调节.Survivin也是胚胎发育早期过程中调节细胞分裂分化的一类重要的因子.对Survivin的研究对于肿瘤治疗的研究及揭示胚胎早期的发育机制有重要的意义.     

杆状病毒p35蛋白抗凋亡作用及机理

杆状病毒入侵可以诱导昆虫细胞凋亡,作为对抗宿主防御体系的一种策略,病毒自身编码具有抗细胞凋亡活性的蛋白,如p35蛋白和IAP。杆状病毒p35蛋白是一种广泛有效的凋亡抑制因子,能在哺乳纲、昆虫纲和线虫纲中抑制细胞凋亡作用,推测其与细胞凋亡途径上保守的成分Caspase起作用。研究表明,p35蛋白正是通过蛋白酶间的相互作用和p35蛋白的剪切而起作用的。就最近几年在p35蛋白抗凋亡作用机理方面的研究作一综述 。     

突变p53功能研究新进展与个性化的肿瘤治疗新策略

p53是迄今为止研究最多的一种抑癌蛋白,最新研究仍在不断地揭示p53在调控机体代谢、生殖方面的新功能。同时,也揭示了不同p53突变蛋白的获得性新功能在肿瘤发生中的促进作用。这些研究对于了解p53突变的个性化新功能,寻找再激活野生型p53,校正突变p53的新途径奠定了基础,不同突变p53蛋白的个性化治疗将是未来肿瘤治疗的热点。文章综述了已发现的一些突变p53的获得性新功能,及针对不同的p53功能缺陷进行的p53蛋白功能再激活的策略:通过小分子或多肽再激活肿瘤细胞中的p53突变蛋白的野生型功能;通过重组的腺病毒在肿瘤细胞中表达野生型p53蛋白;通过抑制MDM2与p53的相互作用稳定野生型p53蛋白。对p53不同位点突变的深入研究可以帮助我们制定更合理的个性化治疗方案,寻求更有效的肿瘤治疗新途径。     

肿瘤治疗中细胞因子递送策略的研究进展

细胞因子多数是由机体免疫细胞和某些非免疫细胞产生的,对细胞的生长、增殖、分化均有调节作用的一类具有生物活性的蛋白质。在肿瘤治疗中,细胞因子作为一种蛋白质药物,具有体内半衰期短、全身毒副作用大等特点,因而选择细胞因子递送策略时需考虑以上因素。文章简要介绍了几种常见的细胞因子,并综述了近年来在肿瘤治疗中细胞因子递送策略的研究进展。     

Immunotherapy approach with recombinant survivin adjuvanted with alum and MIP suppresses tumor growth in murine model of breast cancer

Survivin has received attention as a potential target for cancer immunotherapy because of its crucial role in oncogenesis. We undertook this study to evaluate the immunotherapeutic potential of combination of recombinant survivin along with adjuvant alum and immune modulator Mycobacterium indicus pranii (MIP). In vivo efficacy of the combination was studied in an invasive murine breast cancer model. Recombinant survivin protein was purified from Escherichia coli based expression system and characterized by western blotting. Purified survivin protein was combined with alum and MIP and was used for immunization of Balb/c mice. Antigen-primed animals were then challenged with syngeneic mammary tumor cells known as 4T-1. Balb/c mice spontaneously develop tumor when inoculated with 4T-1 cells. Antigen and adjuvant combination was immunogenic and significantly suppressed tumor growth in mice immunized with combination of recombinant survivin (10?µg), alum, and MIP. This is the first report that describes a combination immunotherapy approach using recombinant survivin, alum, and MIP in highly metastatic murine breast cancer model and holds promise for development of new biotherapeutics for cancer.     

Knockdown of survivin expression by siRNAs enhances chemosensitivity of prostate cancer cells and attenuates its tumorigenicity

Survivin, a member of inhibitor of apoptosis family protein, has become an attractive therapeutic target in cancer due to its selective expression in tumor cells and its important roles for tumor cell viability. Here, we show that vector-based small interfering RNAs （siRNAs） silenced survivin expression in prostate cancer cells, resulting in significantly reduced cell proliferation and enhanced apoptosis, and increased the sensitivity of prostate cancer cells （PC-3） to the apoptosis-inducing agent, platinol. Furthermore, PC-3 cells transfected with the siRNA-expressing vector showed lower tumor formation in nude mice xenografts in vivo. These results demonstrated that inhibition of survivin expression by siRNA attenuated the malignant phenotypes of prostate cancer cells, and may provide a novel approach for gene therapy of androgen-independent prostate cancer.     

Systems biology approaches to develop innovative strategies for lung cancer therapy

Lung cancer (LC) is a number one killer of cancer-related death among men and women worldwide. Major advances have been made in the diagnosis, staging and use of surgery for LC, but systemic chemotherapy and radiotherapy alone or in combination with some targeted agents remains the core treatment of advanced LC. Unfortunately, in spite of improved diagnosis, surgical methods and new treatments, mortality is still extremely high among LC patients. To understand the precise functioning of signaling pathways associated with resistance to current treatments in LC, as well as to identify novel treatment regimens, a holistic approach to analyze signaling networks should be applied. Here, we describe systems biology-based approaches to generate biomarkers and novel therapeutic targets in LC, as well as how this may contribute to personalized treatment for this malignancy.     

放射治疗联合血管内皮抑制素对大鼠移植性肝癌的治疗作用

目的:探讨放射治疗联合血管内皮抑制素对大鼠移植性肝癌的治疗作用。方法:SD大鼠随机分为5组:假手术组,模型组,血管内皮抑素组,放疗组,联合组,血管内皮抑素组和联合组每日尾静脉注射浓度为10%重组人血管内皮抑素0.1 ml(20μg),共12天,联合组在第5天～10天时给予放射治疗,1次/2天。各组动物于移植术后12d处死,分离肿瘤组织备用。结果:血管内皮抑素组、放疗组、联合组均能显著抑制肿瘤生长,抑制VEGF表达,其中联合组抑制效果更为明显。结论:放射治疗联合血管内皮抑制素有明显肿瘤抑制作用,其机制可能与下调VEGF的表达有关。     

适配体在肿瘤治疗方面的应用

适配体（aptamer）是一种可通过指数富集配体系统进化（systematic evolution of ligands by exponential enrichment, SELEX）技术获得的寡聚核苷酸序列,在药物递送、肿瘤诊断及治疗方面有良好的应用前景。本文从适配体的性质、制备等方面出发,简要综述了其作为载体、靶向因子和分子探针在肿瘤治疗中的作用的研究进展。     

Proteomics: a strategy to understand the novel targets in protein misfolding and cancer therapy

Proteins carry out important functions as they fold themselves. Protein misfolding occurs during different biochemical processes and may lead to the development of diseases such as cancer, which is characterized by genetic instability. The cancer microenvironment exposes malignant cells to a variety of stressful conditions that may further promote protein misfolding. Tumor development and progression often arises from mutations that interfere with the appropriate function of tumor-suppressor proteins and oncogenes. These may be due to alteration of catalytic activity of the protein, loss of binding sites for effector proteins or alterations of the native folded protein conformation. Src family kinases, p53, mTOR and C-terminus of HSC70 interacting protein (CHIPs) are some examples associated with protein misfolding and tumorigenesis. Molecular chaperones, such as heat-shock protein (HSP)70 and HSP90, assist protein folding and recognize target misfolded proteins for degradation. It is likely that this misfolding in cancer is linked by common principles, and may, therefore, present an exciting possibility to identify common targets for therapeutic intervention. Here we aim to review a number of examples that show how alterations in the folding of tumor-suppressor proteins or oncogenes lead to tumorigenesis. The possibility of targeting the targets to repair or degrade protein misfolding in cancer therapy is discussed.     

Isolation and characterization of a novel Bacillus thuringiensis strain expressing a novel crystal protein with cytocidal activity against human cancer cells

AIMS: To characterize a novel, unusual, Bacillus thuringiensis strain, to clone its Cry gene and determine the spectrum of action of the encoded Cry protein. METHODS AND RESULTS: The B. thuringiensis strain, referred to as M15, was isolated from dead two-spotted spider mites (Tetranychus urticae Koch; Arthropoda: Arachnida: Tetranychidae). It is an autoagglutination-positive strain and is therefore non-serotypeable. A sporulated culture produces a roughly spherical parasporal inclusion body, the crystal, tightly coupled to the spore. Although the crystal appears to be composed of at least two major polypeptides of 86 and 79 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Southern hybridization indicates that the corresponding crystal protein gene is likely present in only one copy. The crystal protein gene was cloned and, based on nucleotide sequence homology with an orthologous cry31Aa1 gene, assigned the name cry31Aa2. Although initially isolated from spider mites, B. thuringiensis M15 is non-toxic to spider mites and it does not produce the wide spectrum beta-exotoxin. Assays on mammalian cells, however, reveal that Cry31Aa2, when cleaved with trypsin, is cytocidal to some human cancer cells but not to normal human cells. No cytocidal activity was induced after protease treatment of Cry31Aa2 with either chymotrypsin or proteinase K. Trypsin, chymotrypsin and proteinase K cleavage sites were determined. CONCLUSIONS: The B. thuringiensis strain M15 exhibits specific cytocidal activities against some human cancer cells. Significance and Impact of the Study: This study raises questions as to the actual role of this bacterial strain and its crystal protein in the environment. It may be possible to further develop the Cry31Aa2 protein to target specific human cancer cells.     

Inhibition of fibroblast growth factor 2-induced apoptosis involves survivin expression, protein kinase C alpha activation and subcellular translocation of Smac in human small cell lung cancer cells

To investigate the mechanism by which fibroblast growth factor 2 (FGF-2) inhibits apoptosis in the human small cell lung cancer cell line H446 subjected to serum starvation, apoptosis was evaluated by flow cytometry, Hoechst 33258 staining, caspase-3 activity, and DNA fragmentation. Survivin expression induced by FGF-2 and protein kinase Cα (PKCα) translocation was detected by subcellular frac-tionation and Western blot analysis. In addition, FGF-2-in-duced release of Smac from mitochondria to the cytoplasm was analyzed by Western blotting and immunofluorescence. FGF-2 reduced apoptosis induced by serum starvation and up-regulated survivin expression in H446 cells in a dose-dependent andtime-dependentmanner, andinhibitedcaspase-3 activity. FGF-2 also inhibited the release of Smac from mitochondria to the cytoplasm induced by serum starvation and increased PKCα translocation from the cytoplasm to the cell membrane. In addition, PKC inhibitor inhibited the expression of survivin. FGF-2 up-regulates the expression of survivin protein in H446 cells and blocks the release of Smac from mitochondria to the cytoplasm. PKCα regulated FGF-2-induced survivin expression. Thus, survivin, Smac, and PKCα might play important roles in the inhibition of apoptosis by FGF-2 in human small cell lung cancer cells.