微管不稳定蛋白Stathmin--肿瘤基因治疗新靶点

微管不稳定蛋白Stathmin在细胞周期的不同阶段对微运动力平衡的调节发挥重要作用。多种恶性肿瘤中Stathmin都有高水平表达，抑制其表达可以干扰恶性细胞的细胞分裂、Stathmin的过表达可干扰紫杉醇与微管的结合，但增加长春碱类药物与微管的结合能力，临床用药时应予考虑。另外．Stathmin为肿瘤基因治疗提供了一个分子新靶点，腺病毒介导抗stathmin核酶治疗联合察素药物治疗可能获得更强有力的抗增殖和抗肿瘤效应。     

Stathmin蛋白的研究进展

Stathmin蛋白由于其特有的微管解聚活性,在细胞的增殖和分化及肿瘤发生中有十分重要的作用.抑制Stathmin蛋白的表达已经成为肿瘤基因治疗的新的靶点,并且已经证实Stathmin蛋白能够影响某些作用于微管的化疗药物的疗效,对于指导临床用药有一定的意义.Stathmin蛋白还能够促进神经系统的发育,因此受到更多的关注.     

长春瑞滨联合顺铂治疗晚期NSCLC 32例

长春瑞滨(NVB)是一种半合成的长春花生物碱，系细胞周期特异性药物。能抑制细胞内微管蛋白的聚合，阻止增殖细胞有丝分裂中纺锤体的形成，使细胞分裂停止于有丝分裂中期，从而抑制肿瘤细胞的增殖。抗肿瘤效果优于其他长春碱类药物。我们采用NVB联合顺铂治疗晚期非小细胞肺癌     

长春瑞宾外渗致皮肤坏死的护理

长春瑞宾又名去甲长春花碱,商品名盖诺,属细胞周期特异性药物,主要作用于肿瘤细胞的DNA合成后期,阻止微管蛋白聚合形成微管,同时诱导微管解聚,使肿瘤细胞的有丝分裂增殖停止于有丝分裂的中期,达到抗肿瘤目的.     

Stathmin基因在人成骨肉瘤细胞中的表达及意义

stathmin作为细胞信号转导分子在细胞分化及恶性肿瘤发生、发展上发挥重要作用。本研究旨在探讨Stathmin基因在人成骨肉瘤细胞中的表达,并探讨阻断其表达对该肿瘤细胞的生物学行为的影响。方法：RT-PCR及原位杂交法检测2个人成骨肉瘤细胞系及45例人成骨肉瘤组织中Stathmin基因表达情况;以高表达Stathmin基因的人成骨肉瘤细胞系SOSP-9607为靶细胞、反义Stathmin(ASODN)为阻断剂,通过MTT实验观察ASODN对该细胞系的生长抑制作用,并用流式细胞仪分析其对细胞增殖周期的影响。     

泰素为主的联合化疗治疗晚期乳腺癌的临床研究

 泰素系植物类抗癌药，其抗癌机理在于它能够促使微管聚合，形成稳定的不具活性的微管聚合物，从而影响肿瘤细胞的有丝分裂，造成细胞死亡。本文简要报告50例晚期或复发的乳腺癌患者行以泰素为主的联合化疗结果如下：     

微管与微管靶点药物

微管靶点药物是抗肿瘤药物的重要组成部分。以往认为此类药物是通过增加或减少细胞的微管束起作用的，现有研究认为，低浓度的微管靶点药物通过抑制微管动力使有丝分裂受阻，细胞凋亡。现就微管及其聚合动力与几种微管靶点药物的不同作用机制作一综述。     

凋亡抑制因子存活素的研究进展

凋亡抑制因子存活素(survivin)在细胞中呈周期依赖性表达,与有丝分裂期纺锤体微管相互作用,调节G2／M期,并可直接抑制caspase-3和caspase-7的活性。在肿瘤发生发展中,存活素与肿瘤细胞的凋亡负相关,与细胞增殖活性和血管生成正相关。在人类肿瘤中,存活素表达上调可预示生存期缩短和预后不良。体内、外研究中应用存活素反义核酸和突变体可诱导肿瘤细胞凋亡,使肿瘤细胞的生长减弱,并可增加肿瘤细胞对化疗和X射线辐射的敏感性。提示存活素可能是肿瘤诊断和治疗的新靶点。     

紫杉醇与肿瘤免疫的研究进展

紫杉醇（paclitaxel, PTX）是一种有丝分裂抑制剂,通过促进微管蛋白聚合、抑制解聚、保持微管蛋白稳定、抑制细胞有丝分裂和促进肿瘤细胞凋亡发挥抗肿瘤作用。通过研究紫杉醇的结构和功能,发现紫杉醇对免疫细胞包括效应性T细胞、树突状细胞（dendritic cell, DC）、自然杀伤细胞（Natural cell, NK）、调节性T细胞（regulatory T cell, Treg）和巨噬细胞（macrophage）等具有广泛调节作用,紫杉醇杀伤肿瘤细胞的同时逆转肿瘤的免疫逃逸。紫杉醇与过继细胞免疫治疗联合可减轻化疗的不良反应、增加化疗效果。紫杉醇在非小细胞肺癌化疗中抑制调节性T细胞的数量和功能,在乳腺癌化疗过程中增强NK细胞抗肿瘤活性,在卵巢癌化疗中增加肿瘤抗原的免疫原性及促进DC的抗原提呈作用。总之,紫杉醇的免疫调节功能在抗肿瘤领域有广泛的应用前景。     

紫杉醇耐药与β微管蛋白Ⅲ研究进展

 紫杉醇依赖于促进微管聚合,抑制微管解聚,诱导肿瘤细胞凋亡,但肿瘤细胞对紫杉醇的耐药性是限制其临床应用的重要因素。一些基础、临床研究均证实β微管蛋白Ⅲ高表达与紫杉醇耐药、预后不良密切相关。     

癌症相关基因与精神疾病的关联

Stathmin,RIN1和DRD2基因被发现是癌症相关基因,这些基因在乳腺癌,宫颈癌,肝癌等癌细胞中高表达.研究发现Stathmin在情感相关脑区海马及杏仁核高度表达,是参与恐惧记忆调节的基因;RIN1高表达于端脑抑制恐惧记忆的获得;DRD2基因调控多巴胺D2受体表达,该基因失调会导致多巴胺功能紊乱,引起酒精依赖.从而证明这些基因与创伤后应激反应(post traumatic stress disorder,PTSD),精神分裂,抑郁症等精神疾病存在着紧密联系.本文从Stathmin,RIN1,DRD2基因入手,重点阐述这些癌症相关基因在精神疾病中的表现,从基因角度为寻求癌症与精神性疾病之间的关联提供证据.     

Stathmin蛋白:一个潜在的肿瘤标志物

人stathmin也称原癌基因蛋白18(oncogene protein 18, Op18), 是一种广泛存在于细胞质的蛋白质,其相对分子质量约为19×10~3,可与微管蛋白结合,参与微管和纺锤体的组装;与细胞的增殖、分化、再生和运动均有关,并具有信号活性调节的功能.近年来有研究发现,stathmin在多种肿瘤中高表达,并可通过调节微管的解聚,促进肿瘤细胞的运动及侵袭.Stathmin翻译后修饰状态的改变,可影响与p53蛋白的相互作用,参与肿瘤的发生发展.目前单独或者联合化疗药物使用的抗stathmin效应剂已用于某些肿瘤的治疗.虽然stathmin与肿瘤病因学的内在联系尚不十分清楚,但其作为一个潜在的肿瘤标志物或药物靶点值得进一步研究探讨.     

A combination of paclitaxel and siRNA-mediated silencing of Stathmin inhibits growth and promotes apoptosis of nasopharyngeal carcinoma cells

Background

Stathmin, a microtubule associated protein (MAP), is an important molecular target for cancer therapy. Paclitaxel is one of the primary antitumor drugs targeting microtubules (MTs). We hypothesized that decreasing the expression level of Stathmin might improve the effectiveness of paclitaxel in the treatment of nasopharyngeal carcinoma (NPC).

Methods

NPC cell lines, CNE1-LMP1 and HNE2, and a CNE1-LMP1 tumor xenograft mouse model were used to test both in vitro and in vivo our siRNA-based Stathmin silencing strategy. The effects of Stathmin silencing on cell proliferation, apoptosis, and viability were investigated using MTT, AO/EB staining, TUNEL, caspase protein detection, and FCM assays. Cell migration and invasion were assayed using a Transwell assay. The combined effects of Stathmin silencing and paclitaxel were investigated using MTT, FCM, Western blot and indirect immunofluorescence assays. The effect of paclitaxel on Stathmin expression in NPC cells and, in addition, A375, MGC and HeLa cells was determined by RT-PCR and Western blotting.

Results

We found that siRNA-mediated silencing of Stathmin suppresses proliferation, induces apoptosis through the mitochondrial pathway, and causes G2/M-phase cell cycle arrest in the NPC cell lines CNE1-LMP1 and HNE2. Also, the migration and invasion of the respective NPC cells were found to be inhibited. In addition, we show that a combination of Stathmin silencing and paclitaxel is more effective than either agent alone in inhibiting proliferation and inducing apoptosis, cell cycle arrest, and MT polymerization. Furthermore, we found that Stathmin expression in the tumor cells is down-regulated by paclitaxel treatment.

Conclusion

siRNA-mediated silencing of Stathmin suppresses the proliferation, invasion and metastasis, and induces the apoptosis of NPC cells. Paclitaxel reduces the expression of Stathmin, and combining Stathmin silencing with paclitaxel treatment enhances MT polymerization. This combined strategy may provide a new approach for clinical NPC treatment.     

Stathmin在上皮性卵巢癌组织中的表达及意义

背景与目的:Stathmin是一种重要的微管调节蛋白,参与多种肿瘤的发生、发展.本研究旨在验证并探讨Stathmin在上皮性卵巢癌中的表达及意义.方法:利用免疫组化和逆转录聚合酶链反应(RT-PCR)方法检测22例卵巢正常上皮组织,16例良性肿瘤和50例上皮性卵巢癌组织中Stathmin的表达.结果:上皮性卵巢癌中Stathmin mRNA的表达明显高于卵巢良性肿瘤(P<0.05)和正常卵巢上皮(PO.05).进一步利用x2检验统计分析得出,Stathmin蛋白与卵巢癌的临床分期、病理分级、淋巴转移相关(P<0.05),而与年龄、病理类型及腹水量无相关性(P>0.05).结论:Stathmin在上皮性卵巢癌中高表达,可能与卵巢癌的发生、发展相关.     

Stathmin 基因在非小细胞肺癌中的表达

目的：检测 Stathmin 基因在非小细胞肺癌组织中的表达,探讨其与临床病理因素的关系。方法：用免疫组织化学 SP 法检测135例非小细胞肺癌及20例癌旁肺组织中 Stathmin 蛋白的表达,分析其与患者年龄、性别、肿瘤分化程度等临床病理特征之间的相关性。结果：小细胞肺癌组织中 Stathmin 基因蛋白的表达水平明显高于癌旁肺组织（P ＜0．05）,Stathmin 的表达与淋巴结转移有关（P ＜0．05）。结论：Stathmin 基因在非小细胞肺癌组织中的表达显著上调;Stathmin 基因的表达与淋巴结转移有关,而与年龄、性别、肿瘤大小、TNM分期、组织类型无关。     

Stathmin is a Marker of Progression and Poor Prognosis in Esophageal Carcinoma

Stathmin, also called oncoprotein 18, is a founding member of the family of microtubule-destabilizing proteinsthat play a critical role in the regulation of mitosis. At the same time stathmin has been recognized as one ofresponsible factors in cancer cells. The aim of this study was to assess stathmin status, its correlations withclinicopathological parameters and its role as a progosnostic marker in EC patients. The protein and mRNAlevels of stathmin were examined byimmunohistochemistry (IHC) and in situ hybridization in 100EC tissuesand adjacent noncancerous tissues. mRNA and protein expression of stathmin in three EC cell lines(EC9706,ECa109, EC1 commonly used in research) were also analyzed using immunocytochemistry, western blot andin situ hybridization. The prognostic value of Stathmin expression within the tumor tissues were assessed byCox regression and Kaplan-Meier analysis. We showed that stathmin expression was significantly higher in ECtissues than in adjacent noncancerous tissues. High stathmin immunostaining score in the EC was positivelycorrelated with tumor differentiation, Tumor invasion, Lymph node metastases, and TNM stage. In addition, wedemonstrated that three EC cell lines examined, were constitutively expressing a high level of stathmin. Of those,EC-1 showed the strongest mRNA and protein expression for the stathmin analyzed. Kaplan-Meier analysisshowed that significantly longer 5-year survival rate was seen in EC patients with high Stathmin expression,compared to those with low expression of Stathmin expression. Furthermore, multivariate Cox proportionalhazard analyses revealed that Stathmin was an independent factors affecting the overall survival probability.In conclusion, our data provide a basis for the concept that stathmin might be associated with EC developmentand progression.. High levels of Stathmin expression in the tumor tissues may be a good prognostic marker forpatients with EC.     

Stathmin在Ⅳ期非小细胞肺癌中表达及紫杉类化疗耐药相关性研究

目的:探讨Ⅳ期非小细胞肺癌（NSCLC ）Stathmin 蛋白表达与紫杉类化疗耐药性关系。方法:回顾性分析2003年10月～2007年10月75例接受以紫杉类化疗的Ⅳ期NSCLC 临床病理资料。免疫组织化学法检测肿瘤标本Stathmin 蛋白表达,并对化疗疗效及生存时间进行分析。结果:Stathmin 阳性表达（≥50% 阳性染色细胞）率为80.00% 60/75）,男性高表达率为81.63% ,女性为76.92% ,P=0.627;鳞癌71.79% ,腺癌88.89% ,P=0.064;≥58岁78.95% ,<58岁81.08% ,P=0.817;化疗有效率（CR+PR）为34.67% ,Stathmin 高表达患者紫杉类化疗有效率低28.33%（17/60）,进展率高21.67%（13/60）,而Stathmin 低表达患者化疗有效率高60.00%（9/15）,进展率低0（0/15）,P=0.021和P=0.047。Stathmin 高表达者有较短的中位OS（12.0 个月）和PFS（8.0 个月）,而Stathmin 低表达患者有较长的中位OS（17.0 个月）和PFS（13.0 个月）,P=0.008 和P=0.008。患者性别、年龄和组织类型与中位OS及PFS 无相关性,P 值均>0.05。结论:Stathmin 高表达NSCLC 患者对紫杉类药物耐药且预后不良。      

Stathmin 1 is involved in the highly proliferative phenotype of high-risk myelodysplastic syndromes and acute leukemia cells

Stathmin 1 is an important cytoplasmic microtubule-destabilizing protein that plays critical roles in proliferation and accurate chromosome segregation through regulation of microtubule dynamics. High levels of Stathmin 1 expression have been reported in leukemia and solid tumors. However, Stathmin 1 has not been studied in myelodysplastic syndrome cells. We, herein, report that significantly higher Stathmin 1 levels were observed in proliferating hematopoietic cells, in high-risk MDS and acute leukemia cells. In addition, Stathmin 1 silencing in U937 and Namalwa leukemia cells reduced cell proliferation and clonogenicity. Our data suggest that Stathmin 1 expression may be related to the highly proliferative phenotype of hematopoietic cells and add new insights into the participation of Stathmin 1 in hematological malignancies.     

微管解聚蛋白Ｓｔａｔｈｍｉｎ与肿瘤相关性的研究进展

微管解聚蛋白Ｓｔａｔｈｍｉｎ具有微管解聚活性,在细胞周期的转换过程中起着重要作用。在多种恶性肿瘤细胞中都可以检测到Ｓｔａｔｈｍｉｎ高表达。已有研究证实,Ｓｔａｔｈｍｉｎ蛋白的高表达能够影响某些作用于微管的化疗药物的疗效,抑制其表达可以提高这些药物的疗效。Ｓｔａｔｈｍｉｎ基因为肿瘤基因治疗提供了新的分子靶点。