丝切蛋白-1和内皮细胞分化因子受体-1的研究进展

丝切蛋白(Cofilin,CFL)是一种肌动蛋白结合蛋白,存在于真核生物中,通过肌动蛋白纤维解聚作用,可以使肌动蛋白重复使用,以确保快速的肌动蛋白纤维聚合/解聚,从而改变细胞和细胞外基质之间的粘附,并最终促进细胞迁移和运动。CFL-1是丝切蛋白家族的重要成员,其活性影响着细胞内信号转导以及细胞骨架肌动蛋白重组,与肿瘤细胞的迁移和侵袭有关,可能是恶性肿瘤的一个潜在治疗靶点。内皮细胞分化因子受体-1(EDG-1)可通过激活促分裂原活化蛋白激酶(MAPK)、磷脂酰肌3激酶(PI3K)、丝氨酸/苏氨酸蛋白激酶(Akt)和Rho等信号分子而发挥生物学效应,在细胞的增殖和移动、心血管系统、免疫系统等多方面发挥着重要的作用,特别是在肿瘤的发生、发展、浸润、转移过程中的作用受到日益广泛的重视。关于EDG-1的相关研究表明,EDG-1将可能成为一个新的肿瘤靶向治疗的潜在靶点。本文综述了CFL-1与EDG-1这两个可能成为恶性肿瘤治疗靶点分子的最新研究进展。     

整联蛋白的功能

整联蛋白（integrins）是广泛存在于真核细胞表面的完整的膜受体家族，因可介导细胞与细胞外基质的黏附，使细胞得以附着形成整体而得名。目前已知至少有18种不同的α亚基和8种β亚基形成的20多种αβ异二聚体。整联蛋白配体主要有胶原蛋白、纤维结合蛋白、层粘连蛋白、玻连蛋白、血小板凝血酶敏感蛋白、胞间黏附分子、细胞反受体、补体蛋白，以及多种细菌和病毒蛋白，在介导血管内皮细胞和肿瘤细胞的黏附、淋巴细胞运输、肿瘤生长及感染等都有重要的作用。目前应用抗体或合成肽来干扰整联蛋白的功能，已经用于血栓症、炎症、癌症的治疗。     

钙网织蛋白在肿瘤发生发展中的作用研究进展

钙网织蛋白(CRT)是一种内质网Ca~(2+)结合伴侣蛋白,参与调节细胞的许多生理功能,包括调节细胞内Ca~(2+)动态平衡、氧化应激反应以及凝集素结合反应,调控细胞的粘附力、细胞间相互作用、细胞迁移、吞噬作用、整合素依赖的Ca~(2+)信号传导以及免疫反应,确保新合成的蛋白质的正确折叠及糖蛋白的形成等。CRT还参与细胞的许多病理反应过程,近年来许多研究表明CRT与肿瘤细胞的增殖、分化、凋亡、粘附、侵袭、迁移、吞噬等过程密切相关,可以作为一种潜在的肿瘤诊断分子标记和癌症治疗的靶标。我们将对CRT在肿瘤发生发展中的研究进展进行综述。     

桩蛋白 血管内皮生长因子在胃癌组织中的表达及意义

桩蛋白是近年来发现的一种重要的细胞黏附因子,是致癌性酪氨酸激酶的一种底物,与整合素相关联,构成细胞与细胞外基质局部黏附关键部位,调节细胞的移动和播散等功能,从而提高肿瘤细胞转移和侵袭的能力。     

加味柴胡桂姜汤介导乳腺癌细胞黏附分子PSGL-1改善炎症-黏附-转移作用研究

目的 研究炎症微环境下黏附分子PSGL-1异常表达对乳腺癌细胞增殖、黏附、侵袭及迁移能力的影响及加味柴胡桂姜汤干预作用机制。方法 制备加味柴胡桂姜汤含药血清,选择高转移乳腺癌MDA-MB-231细胞株,筛选药物最佳浓度;运用脂多糖刺激乳腺癌细胞形成炎症微环境模型,将细胞分为空白对照组、LPS模型组、顺铂组、PSGL-1中和抗体组、加味柴胡桂姜汤组、加味柴胡桂姜汤与PSGL-1中和抗体联合组,采用CCK-8法、明胶黏附、Transwell及细胞划痕实验检测细胞增殖、黏附、侵袭和迁移能力;qRT-PCR和Western blot实验检测PSGL-1与其受体及Vimentin等EMT相关基因表达。结果 LPS刺激乳腺癌细胞后细胞生物学行为改变,黏附分子及EMT基因表达增加,加味柴胡桂姜汤、PSGL-1中和抗体均能抑制LPS诱导的增强作用,联合组较加味柴胡桂姜汤组抑制作用降低。结论 炎症微环境下肿瘤细胞侵袭及迁移能力增强,加味柴胡桂姜汤能够靶向调控PSGL-1抑制乳腺癌细胞侵袭及迁移。     

LIM激酶与肿瘤迁移、侵袭的研究进展

肿瘤细胞增殖及迁移、侵袭是影响恶性肿瘤患者预后的重要因素,受到多种基因的调控。目前发现各种肌动蛋白结合蛋白能通过调节细胞骨架运动调节肿瘤细胞的增殖、迁移、侵袭过程。肌动蛋白解聚因子丝切蛋白家系（ADF/cofilin）是广泛存在于真核生物中的一种肌动蛋白结合蛋白,通过解聚肌动蛋白发挥生物学作用。而LIM激酶（LIMKs）通过磷酸化ADF/cofilin ,使其失活进而丧失解聚肌动蛋白的能力,改变细胞形态、黏附及运动。近年来,LIM激酶的这一作用逐渐被国内外研究者所认知,并运用到肿瘤细胞的发生机制研究中。     

基质相互作用蛋白分子1在肿瘤发生发展和 临床应用中的研究进展

基质相互作用蛋白分子1（STIM1）与肿瘤的发生发展密切相关,其参与多种癌症细胞凋亡、增殖、迁移和侵袭的调节过程。阻断或敲除STIM1可以显著抑制癌细胞的增殖和迁移。阐明STIM1在癌症细胞中的调节机制,将有助于新的治疗靶点的确定。本文对STIM1分子在不同肿瘤中的作用机制及临床应用前景作一综述。     

灵菌红素体外对肿瘤转移相关生物学行为的影响

目的探明灵菌红素(Metacycloprodigiosin,MP)对肿瘤转移相关生物学行为的影响。方法利用MTT法检测MP对HUVEC和4TO7细胞增殖的影响;划痕法检测其对HUVEC细胞迁移能力的影响;Matrigel模仿基底膜检测MP对HUVEC细胞管腔形成的影响;黏附实验检测MP对4TO7细胞黏附能力的影响;划痕法及Transwell小室法分别检测MP对4TO7细胞迁移及侵袭能力的影响。结果MP在小于10μmol·L-1的浓度下对HUVEC及4TO7细胞增殖能力无影响,在0.01、0.1、1μmol·L-1浓度下能抑制HUVEC细胞的迁移及管腔形成,并且能明显抑制4TO7细胞的黏附、迁移和侵袭。结论MP可能通过抑制血管内皮细胞管腔形成,以及影响肿瘤细胞黏附、迁移及侵袭,进而抑制肿瘤的转移。     

p21活化激酶抑制剂的研究进展

p21活化激酶(PAKs)是肿瘤细胞内信号网络的关键调节因子之一,其可以通过众多的下游结合蛋白,对肿瘤细胞的生存、伪足形成、细胞周期、细胞侵袭和迁移等众多生物学功能发挥调节作用,因此,目前已成为肿瘤治疗的新靶点。本文对近年来PAKs及其抑制剂研究的最新进展进行综述,以期为新型抗肿瘤药物的研发提供参考依据。     

筋骨草和茯苓配伍合用抑制乳腺癌细胞侵袭转移作用及初步机制研究

目的研究筋骨草和茯苓联合用药对高转移性乳腺癌MDA-MB-231(三阴型乳腺癌)和SK-BR-3(HER-2过表达乳腺癌)细胞侵袭转移的作用及分子机制。方法以筋骨草有效部位——总环烯醚萜类化合物和茯苓有效部位——三萜类化合物为研究对象。采用细胞黏附实验、细胞划痕和Transwell侵袭实验检测细胞黏附、运动和侵袭能力。Western blot法检测上皮-间质转化(epithelial-mesenchymal transitions,EMT)相关蛋白和MAPK通路蛋白表达。结果筋骨草和茯苓合用对MDA-MB-231和SK-BR-3细胞的黏附、迁移和侵袭能力有明显的抑制作用,配伍比例为10∶1时具有较好的协同效应。两药合用还可逆转乳腺癌细胞EMT,主要表现在上皮性标志物β-catenin、E-cadherin、ZO-1表达增加,间质性标志物Vimentin表达降低。进一步研究发现,两药合用明显降低p-ERK1/2、p-JNK和p-p38的蛋白表达。结论筋骨草和茯苓合用能有效地抑制高转移性乳腺癌MDA-MB-231和SK-BR-3细胞的侵袭和转移,作用机制可能与其调控MAPK通路,逆转肿瘤细胞EMT有关。     

Brefeldin A Induces Apoptosis by Activating the Mitochondrial and Death Receptor Pathways and Inhibits Focal Adhesion Kinase‐Mediated Cell Invasion

Brefeldin A induces apoptosis in various cancer cells; however, the apoptotic process in cancer cells exposed to brefeldin A remains unclear. In addition, it is unclear whether brefeldin A‐induced apoptosis is mediated by the formation of reactive oxygen species. Furthermore, the effect of brefeldin A on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effect of brefeldin A on apoptosis, cell adhesion and migration using the human epithelial ovarian carcinoma cell lines OVCAR‐3 and SK‐OV‐3. The results suggest that brefeldin A may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase‐8‐ and Bid‐dependent pathways. The apoptotic effect of brefeldin A seems to be mediated by formation of reactive oxygen species and depletion of GSH, which results in the activation of apoptotic caspases. Brefeldin A inhibited foetal bovine serum‐induced adhesion and migration of OVCAR‐3 cells. Brefeldin A may prevent the foetal bovine serum‐induced cell adhesion and migration by limiting the focal adhesion kinase‐dependent activation of cytoskeletal‐associated components.     

Juice of eclipta prostrata inhibits cell migration in vitro and exhibits anti-angiogenic activity in vivo

BACKGROUND: The invasion of cancer cells is critical for metastasis. The effects of Eclipta prostrata, a Thai medicinal plant, on invasion, migration and adhesion of cancer cells were investigated and the anti-angiogenic activity in vivo was evaluated. MATERIALS AND METHODS: In vitro invasion and migration assays were performed in modified Boyden chambers. In vivo anti-angiogenic activity was determined using the chick chorioallantoic membrane (CAM) assay. RESULTS: E. prostrata juice inhibited cancer invasion and migration, without affecting cell adhesion. Cell migration was inhibited in a variety of cancer cell types and in endothelial cells, with IC50 values of 31-70 microg/ml, much lower than the IC50 values for cytotoxicity of 203-1,217 microg/ml for cancer cells and >4,000 microg/ml for endothelial cells. Fifty percent inhibition of angiogenesis by E. prostrata juice was observed at 200 microg/egg. CONCLUSION: E. prostrata juice inhibited cancer and endothelial cell migration in vitro and also showed in vivo anti-angiogenic activity.     

Involvement of twist in NNK exposure-promoted lung cancer cell migration and invasion

Nicotine-derived nitrosamine ketone (NNK), one of the potent carcinogens in cigarette smoke, has been reported to facilitate lung cancer cell migration and invasion. Twist plays an important role in regulating migration and invasion of lung cancer cells. However, it is unclear whether Twist is implicated in NNK-induced migration and invasion of lung cancer cells. Lung cancer cells were exposed to various doses of NNK for four weeks. The expression levels of protein and mRNA were detected by western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Small interfering RNA (siRNA) was applied to knock down the expression of Twist. The ability of cell migration and invasion was evaluated by wound-healing assay and Transwell invasion assay. NNK exposure increased the levels of Twist protein and mRNA expression in lung cancer cells compared to solvent control. Lung cancer cells exposed to NNK exhibited higher ability of migration and invasion than those with solvent control did. Twist silencing could block NNK-promoted migration and invasion of lung cancer cells. NNK exposure increased the expression levels of N-cadherin mRNA and decreased the expression levels of E-cadherin mRNA in lung cancer cells, which could be modulated by Twist silencing. In conclusion, Twist was involved in NNK-induced migration and invasion of lung cancer cells.     

Menadione induces the formation of reactive oxygen species and depletion of GSH-mediated apoptosis and inhibits the FAK-mediated cell invasion

Menadione induces apoptosis in tumor cells. However, the mechanism of apoptosis in ovarian cancer cells exposed to menadione is not clear. In addition, it is unclear whether menadione-induced apoptosis is mediated by the depletion of glutathione (GSH) contents that is associated with the formation of reactive oxygen species. Furthermore, the effect of menadione on the invasion and migration of human epithelial ovarian cancer cells has not been studied. Therefore, we investigated the effects of menadione exposure on apoptosis, cell adhesion, and cell migration using the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. The results suggest that menadione may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of menadione appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Menadione inhibited fetal-bovine-serum-induced cell adhesion and migration of OVCAR-3 cells, possibly through the suppression the focal adhesion kinase (FAK)-dependent activation of cytoskeletal-associated components. Therefore, menadione might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy.     

羧甲基壳聚糖对人高转移肺癌细胞——95-D增殖能力和体外转移能力的抑制作用

目的评价羧甲基壳聚糖对人高转移肺癌细胞——95-D增殖能力和体外转移能力的抑制作用.方法用软琼脂克隆形成实验、创伤实验、黏附实验和transwell小室实验来评价羧甲基壳聚糖对95-D细胞的影响.结果羧甲基壳聚糖浓度在0～150 μg·ml-1范围内,剂量依赖性地抑制95-D细胞的增殖能力、移动能力、浸润能力、黏附能力和克隆形成能力.结论羧甲基壳聚糖能有效抑制95-D细胞的增殖能力和体外转移能力.     

Rho-kinase inhibitor upregulates migration by altering focal adhesion formation via the Akt pathway in colon cancer cells

Although Rho-kinase is reportedly implicated in carcinogenesis and the progression of human cancers, its precise mechanism has not been fully elucidated. We recently reported that Rho-kinase negatively regulates epidermal growth factor (EGF)-stimulated cancer progression in SW480 colon cancer cells. In the present study, we investigated the effect of Rho-kinase on the migration of SW480 colon cancer cells and the mechanism underlying the involvement of Rho-kinase. Interestingly, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, 2HCl (Y27632), a specific inhibitor of Rho-kinase, dose-dependently enhanced cell migration. SW480 cells spontaneously release vascular endothelial growth factor (VEGF), however, Y27632 had little effect on its release. While Rho-kinase, which is generally phosphorylated in unstimulated cells, was clearly suppressed by Y27632, exogenous VEGF did not affect its phosphorylation. Immunofluorescence microscopy revealed that Y27632 caused a dramatic change in the localization of focal adhesion components, vinculin, phosphorylated caveolin-1 and tyrosine-phosphorylated proteins in SW480 cells. Furthermore, Akt inhibitor restored the loss of vinculin-stained focal adhesion formation induced by Y27632. We also observed similar effects for Y27632 on the migration and localization of focal adhesion components such as vinculin in another colon cancer cell line, HT29. Taken together, these results strongly suggest that Rho-kinase negatively regulates the migration of colon cancer cells by altering focal adhesion formation via the Akt pathway.     

新的抗肿瘤药7-hydroxystaurosporine(UCN-01)抑制肿瘤浸润和转移

目的和方法研究7_hydroxystaurosporine(UCN_01)对转移性前列腺肿瘤DU_145细胞浸润和转移的影响。用体外转移和创伤法检查细胞浸润和转移 ,用Westernblotting 法检查蛋白质的表达。结果UCN_01在非毒性剂量下(100nmol·L -1)明显地抑制DU_145细胞浸润和转移。而且 ,UCN_01这种抗肿瘤浸润和转移功能与它增加细胞_细胞粘连分子E_cadherion的表达有关。结论这些实验首次证实UCN_01能抑制人前列腺肿瘤细胞的浸润和转移。UCN_01的临床应用可能更有效地控制前列腺肿瘤转移     

PSA及NCAM表达差异COS-7细胞的建立及PSA对COS-7细胞迁移侵袭能力的影响

目的构建PSA与NCAM表达差异的COS-7细胞,并检测PSA的表达对细胞粘附、迁移侵袭能力的影响,为今后进一步研究PSA介导的细胞迁移侵袭信号通路变化,阐明PSA对肿瘤转移影响的分子机制奠定基础。方法该文通过双转染质粒构建PSA与NCAM表达差异的COS-7细胞株,利用流式细胞术及Western blot方法检验转染效率;采用MTT法检测PSA表达差异COS-7细胞的增殖;粘附分析法检测COS-7细胞对细胞外基质Fn的粘附能力;利用tran-swell小室比较PSA与NCAM表达差异的COS-7细胞迁移、侵袭能力。结果PSA与NCAM表达差异COS-7细胞构建成功,PSA可降低COS-7细胞与基底膜的粘附,增强其迁移及侵袭能力。结论该文所建立的PSA与NCAM表达差异的COS-7细胞株可用于今后进行PSA对细胞迁移侵袭信号通路影响的机制研究。     

紫花牡荆素对人宫颈癌细胞凋亡和侵袭迁移的影响

目的 观察紫花牡荆素(CAT)对人宫颈癌HeLa和SiHa细胞凋亡和侵袭转移的影响。方法 不同浓度CAT作用于HeLa和SiHa细胞不同时间后,采用MTT法观察药物对细胞活力的影响,流式细胞仪检测凋亡率,划痕试验观察细胞迁移率,基质胶法测定细胞粘附百分率,Transwell试验检测侵袭细胞数,Western blotting分析CAT对SiHa细胞抑制转移蛋白nm23-H1和促转移蛋白MTA1表达的影响。结果 CAT显著抑制HeLa和SiHa细胞活力,增加细胞凋亡率;降低细胞迁移百分率和黏附百分率;减少侵袭细胞数;明显增加SiHa细胞nm23-H1蛋白表达,降低MTA1蛋白表达。结论 CAT显著诱导人宫颈癌HeLa和SiHa细胞凋亡,抑制其侵袭迁移,提示其具有潜在的抗宫颈癌作用。     

整合素α_5β_1与CD_(44)V_3在胃癌中的表达及临床意义

目的本研究旨在探讨整合素α5β1、CD44V3表达水平对胃癌细胞黏附、迁移、髓外浸润过程的影响。方法采用Western blot检测法及RT-PCR分别测量HTB-103、CRL-5822、CRL-5971及CRL-5973等不同对数生长期的胃癌细胞株整合素α5β1、CD44V3蛋白表达水平及整合素α5β1 m RNA、CD44V3 m RNA水平.将不同胃癌细胞株随机分为实验组及对照组,实验组加入整合素α5β1、CD44V3抗体,对照组加入同型Ig G,观察两组胃癌细胞与ECV304细胞系的黏附率、细胞迁移率及胃癌细胞穿过人工基质膜的浸润能力。结果CRL-5822、CRL-5971及CRL-5973细胞整合素α5β1 m RNA相对表达量明显高于HTB-103细胞(P<0.05)。观察组CRL-5822、CRL-5971及CRL-5973细胞株黏附率、迁移率、及浸润率显著低于对照组(P<0.05),而两组HTB-103细胞无统计学差异(P>0.05)。结论整合素α5β1、CD44可能参与胃癌细胞的形成、聚集、生长及浸润的过程,其表达水平与胃癌病程进展具有密切的关系。