Stathmin蛋白——肿瘤治疗的新靶点

Stathmin是一种普遍存在的胞质磷蛋白,在细胞增殖、细胞分化的信号途径和激活中具有多种调节功能,对肿瘤细胞恶性表型的维持、转移、侵犯及分化等起重要作用,能够影响某些作用于微管的化疗药物的疗效.目前足肿瘤研究的热点,Stathmin有可能成为肿瘤新的治疗靶点.     

胃腺癌组织微管解聚蛋白1和突变型P53的表达及意义

目的应用免疫组化方法检测胃腺癌中微管解聚蛋白(Stathmin)1和突变型P53(TP53)的表达,分析二者的关系及意义。方法确诊为胃腺癌的患者共72例为A组,经病理学确诊为胃黏膜高级别上皮内瘤变的术后组织32例为B组,经病理学确诊为胃黏膜低级别上皮内瘤变的内镜咬检组织32例为C组,距肿瘤边缘>5 cm的非肿瘤性胃黏膜组织15例为D组,均留取蜡块组织,应用免疫组化SP法检测4组Stathmin1和TP53的表达。结果 4组Stathmin1和TP53表达的阳性率差异均有统计学意义(P<0.01)。A组Stathmin1和TP53的表达与肿瘤最大径、增殖指数密切相关;Stathmin1的表达与肿瘤脉管侵犯密切相关,二者均与肿瘤的淋巴结转移和神经侵犯无相关性。相关分析显示A组Stathmin1和TP53呈正相关。结论胃腺癌中Stathmin1和TP53高表达对肿瘤形成和进展有重要作用。Stathmin1和TP53有明显的正向协同作用。     

食管鳞癌组织中β微管蛋白Ⅲ、Stathmin和P糖蛋白的表达与预后

目的:探讨食管鳞癌组织中β微管蛋白Ⅲ(β-tubulin Ⅲ)、Stathmin和P糖蛋白(P-gp)的表达与预后及紫杉醇化疗疗效的关系.方法:回顾性分析76例食管鳞癌患者的临床病历资料,采用免疫组织化学方法检测76例鳞癌组织和40例正常食管黏膜组织中β-tubulin Ⅲ、Stathmin和P-gp蛋白的表达,对64例根治术后用含紫杉醇药物行辅助化疗患者的疗效与3种蛋白的表达关系进行分析.结果:食管鳞癌组织中β-tubulin Ⅲ、Stathmin和P-gp蛋白表达阳性率分别为63.2%、54.0%和64.5%,明显高于正常黏膜中的10%、10%和20%(均P=0.000),并且β-tubulin Ⅲ、Stathin及P-gp在低分化、有淋巴结转移及Ⅲ、Ⅳ期肿瘤中阳性率均明显升高,分别为66.7%、77.8%、74.1%;76.9%、69.2%、61.5%;69.2%、61.5%、69.2%(均P<0.05).64例术后用含紫杉醇化疗的患者中β-tubulin Ⅲ、Stathmin及P-gp蛋白阳性组的化疗有效率明显低于阴性组(P值分别为0.024、0.024、0.012).结论:食管癌中β-tubulin Ⅲ、Stathmin和P-gp蛋白阳性率表达均明显升高,预示肿瘤的恶性程度较高且预后差.     

食管鳞癌患者血清Stathmin的表达及临床意义

目的:探讨血清Stathmin的表达水平对食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)的诊断价值及临床意义.方法:采用酶联免疫吸附法(enzyme-linkedimmunosorbent assay,ELISA)检测74例ESCC与81例健康对照血清Stathmin含量;采用ELISA检测34例食管鳞癌与40例健康对照血清角蛋白19片段抗原21-1(cytokeratin 19 fragment antigen 21-1,Cyfra21-1)的水平;采用化学发光法检测血清癌胚抗原(carcinoembryonic antigen,CEA)、癌抗原19-9(cancer antigens19-9,CA19-9)、癌抗原72-4(cancer antigens7 2-4,C A 7 2-4)水平;统计学分析血清中Stathmin浓度与临床参数的相关性.结果:ESCC组血清Stathmin水平显著高于健康对照组(P<0.001),ESCC组血清Stathmin水平与伴有淋巴结转移相关(P=0.036),血清Stathmin水平与患者性别、年龄、分化程度、TNM分期和肿瘤大小无显著相关.比较Stathmin和Cyfra21-1的受试者工作特性曲线(receiver operating characteristic curve,ROC曲线),提示Stathmin的灵敏度和特异性均优于Cyfra21-1,血清Stathmin水平对ESCC的诊断灵敏度可达94.6%.结论:血清Stathmin升高在食管鳞癌的发生发展中起重要作用,食管癌患者血清的Stathmin检测,对ESCC的诊断和预后判定具有一定意义.Stathmin可作为食管鳞癌诊断、治疗和判断预后的一个新的血清标志物,辅助临床诊断.     

Stathmin在非小细胞肺癌组织中的表达及意义

目的探讨Stathmin在非小细胞肺癌发生、发展中的作用。方法采用RT-PCR法检测50份非小细胞肺癌组织及相应癌旁组织、正常肺组织标本中Stathmin的表达情况,分析Stathmin表达与肿瘤细胞分化程度、TNM分期的关系。结果癌组织与癌旁组织中Stathmin阳性表达率均明显高于正常肺组织(P均<0.01)。分化程度低的癌组织statmin阳性表达率明显高于分化程度高的癌组织(P=0.018)。TNM分期越高,Stathmin阳性表达率越高。结论 Stathmin在非小细胞肺癌中呈高表达,其可能作为预示肿瘤恶性程度的参考指标及治疗肿瘤的新分子靶点。     

Stathmin在胃肠道间质瘤组织中的表达与临床病理因素之间的关系

[目的]分析原发性胃肠道间质瘤(GIST)中微管解聚蛋白(Stathmin)的表达程度与临床病理因素之间的相关性,探讨Stathmin是否是GIST患者的诊断、治疗及其预后中发挥重要作用的蛋白。[方法]采用免疫组化学技术检测96例GIST组织中Stathmin蛋白的表达,采用SPSS25.0软件统计分析Stathmin蛋白的表达水平与患者一般临床病理学特征之间的相关性。[结果]Stathmin在GIST组织中阳性率为45.8%(44/96),在GIST组织中高表达;Stathmin阳性表达与患者肿瘤危险度、CD34有统计学意义(P0.05、P0.01),与患者性别、年龄、肿瘤部位、肿块大小、浸润深度等差异无统计学意义(P0.05)。[结论]在GIST患者中Stathmin高表达与肿瘤危险度分级、CD34(+)密切相关。Stathmin有可能成为判别该病的辅助诊断及患者病情恶化的指标,为今后GIST患者的诊断、临床治疗策略及预后判断提供理论依据。     

Stathmin/Oncoprotein 18(Op18)在肝细胞癌中的表达及其意义

目的探讨Stathmin／oncoprotein18（Op18）mRNA和蛋白在肝细胞癌中的表达程度及其与肝癌临床病理特征的关系。方法应用RT—PCR技术检测33例肝癌、相应癌旁组织和肝癌细胞株SMMC7721和HepG2中Stathmin mRNA的水平，同时应用免疫组织化学方法检测了上述组织和细胞株中Stathmin蛋白的表达。结果肝癌组织Stathmin mRNA的表达水平高于相应的癌旁组织（P〈0．05）。肝癌组织Stathmin蛋白的阳性表达率为51．5％，癌旁组织为6％，阳性染色位于胞质内。两种肝癌细胞株中亦有Stathmin表达。Stathmin过表达与肿瘤大小、门脉受侵、TNM分期及Edmondson分级有关（P〈0．05）。结论Stathmin在肝癌中过表达，可能与肝癌的发生及进展有关。     

TGF-β1、TIEG1和Stathmin蛋白在食管鳞状细胞癌组织中的表达及临床意义

目的:探讨转化生长因子-β1(transforming growth factor-β1,TGF-β1)、早期基因1(transforming growth factor β-inducible earlygene1,TIEG1)和Stathmin蛋白在食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)组织中的表达及临床意义.方法:应用免疫组织化学法检测62例ESCC、31例癌旁不典型增生组织及62例正常食管黏膜组织中TGF-β1、TIEG1和Stathmin蛋白的表达情况.结果:正常食管黏膜组织中TGF-β1和TIEG1蛋白表达的阳性率显著高于非典型增生组织和食管癌组织[TGF-β1:62(100.0%)vs22(71.0%),41(66.1%),P<0.05].食管鳞癌组织和癌旁不典型增生组织中也检测到Stathmin蛋白表达,但较TGF-β1和TIEG1表达范围窄.正常食管黏膜组织中未检测到Stathmin的表达.进一步统计分析表明Stathmin与TGF-β1、TIEG1在食管鳞癌的表达呈负相关[TGF-β1:r=-0.609,r=-0.459;TIEG1:P<0.05);高表达Stathmin的病例中TGF-β1和TIEG1低表达或不表达.统计结果还表明TGF-β1、TIEG1和Stathmin蛋白表达与癌的临床分级及淋巴结转移密切相关(P<0.05).结论:TGF-β1和TIEG1蛋白可能结合Stathmin结合位点,负性调节Stathmin蛋白,抑制食管癌的转移.     

Stathmin蛋白在人原发性肝癌中的表达与原发性肝癌生物学行为的关系

目的 探讨Stathmin蛋白在人原发性肝癌中的表达及其与原发性肝癌生物学行为的关系.方法 分别采用免疫组化法和Western blot法检测20例正常肝组织和36例原发性肝癌组织中Stathmin蛋白的表达.结果免疫组化法检测Stathmin蛋白在正常肝组织、低级别原发性肝癌 (Ⅱ级-Ⅲ级)及高级别原发性肝癌(Ⅳ级)组织中阳性表达率分别为20%、65%、100%.Ⅱ级-Ⅲ级组、Ⅳ级组分别与正常肝组织比较,差异均有统计学意义(P<0.05);Ⅱ级-Ⅲ级组与Ⅳ级组比较,差异有统计学意义(P<0.05).Western blot法检测显示,Stathmin蛋白在正常肝组织、Ⅱ级-Ⅲ级组、Ⅳ级组表达相对值分别为0.35±0.16、0.69±0.22、0.91±0.18.Ⅱ级-Ⅲ级组、Ⅳ级组分别与正常肝组织比较,差异均有统计学意义(P<0.01),Ⅱ级-Ⅲ级组与Ⅳ级组比较,差异有统计学意义(P<0.01).结论 Stathmin在原发性肝癌中过表达,与原发性肝癌的发生及发展可能有关.     

Stathmin及Cathepsin B在结直肠癌中的表达

目的研究Stathmin和Cathepsin B在人结直肠癌组织及其转移灶中的表达差异,探讨Stathmin和Cathepsin B在结直肠癌发生发展过程中的作用及其临床病理意义。 方法用免疫组织化学染色技术检测158例高分化,中分化及低分化结直肠癌患者手术切除标本及64例相应转移灶组织中Stathmin蛋白和Cathepsin B蛋白的表达情况。 结果Stathmin蛋白及Cathepsin B蛋白在结直肠癌组织及其转移灶中均高表达(分别为P<0.05及P<0.01);高分化结直肠癌样本中Stathmin蛋白及Cathepsin B蛋白在细胞膜或细胞浆阳性表达,而在低分化结直肠癌细胞核,细胞膜及细胞浆中可见二者的阳性表达。 结论Stathmin及Cathepsin B可能是判断结直肠癌患者临床病理分级的有用指标。     

Stathmin及Cathepsin B在结直肠癌中的表达

目的研究Stathmin和Cathepsin B在人结直肠癌组织及其转移灶中的差异表达,探讨Stathmin和Cathepsin B在结直肠癌发生发展过程中的作用及其临床病理意义。 方法用免疫组织化学染色技术检测158例高分化,中分化及低分化结直肠癌患者手术切除标本及64例相应转移灶组织中Stathmin蛋白和Cathepsin B蛋白的表达情况。 结果Stathmin蛋白及Cathepsin B蛋白在结直肠癌组织及其转移灶中均高表达;高分化结直肠癌样本中Stathmin蛋白及Cathepsin B蛋白在细胞膜或细胞浆阳性表达,而在低分化结直肠癌细胞核,细胞膜及细胞浆中可见二者的阳性表达。 结论Stathmin及Cathepsin B可能是判断结直肠癌患者临床病理分级的有用指标。     

Stathmin expression and megakaryocyte differentiation: a potential role in polyploidy

OBJECTIVE: Megakaryopoiesis is characterized by two major processes, acquisition of lineage-specific markers and polyploidization. Polyploidy is a result of endomitosis, a process that is characterized by continued DNA replication in the presence of abortive mitosis. Stathmin is a major microtubule-regulatory protein that plays an important role in the regulation of the mitotic spindle. Our previous studies had shown that inhibition of stathmin expression in human leukemia cells results in the assembly of atypical mitotic spindles and abnormal exit from mitosis. We hypothesized that the absence of stathmin expression in megakaryocytes might be important for their abortive mitosis. MATERIALS AND METHODS: The experimental models that we used were human K562 and HEL cell lines that can be induced to undergo megakaryocytic differentiation and primary murine megakaryocytes generated by in vitro culture of bone marrow cells. The megakaryocytic phenotype was evaluated by flow cytometry and light microscopy. The DNA content (ploidy) was analyzed by flow cytometry. Stathmin expression was analyzed by Western and Northern blotting and by RT-PCR. RESULTS: Our studies showed an inverse correlation between the level of ploidy and the level of stathmin expression in megakaryocytic cell lines and in primary cells. More importantly, inhibition of stathmin expression in K562 cells enhanced the propensity of these cells to undergo endomitosis and to become polyploid upon induction of megakaryocytic differentiation. In contrast, inhibition of stathmin expression interfered with the ability of the cells to acquire megakaryocyte-specific markers of differentiation. CONCLUSION: Based on these observations, we propose a model of megakaryopoiesis in which stathmin expression is necessary for the proliferation and differentiation of early megakaryoblasts and its suppression in the later stages of megakaryocytic maturation is necessary for polyploidization.     

Stathmin levels in growth plate chondrocytes are modulated by vitamin D3 metabolites and transforming growth factor-beta1 and are associated with proliferation

Stathmin is a highly conserved, phosphorylated cytosolic protein that is found at decreased levels in all cells as they become more terminally differentiated, or when they decrease in their rate of proliferation. This study examined the hypothesis that stathmin levels in growth plate chondrocytes decreases as endochondral maturation increases. To test this hypothesis, we used a costochondral growth plate chondrocyte cell culture model. Cells derived from the resting zone (RC) express twice as much stathmin mRNA in culture and have twice as much stathmin protein as cells derived from the post proliferative growth zone ([GC];prehypertrophic and upper hypertrophic cell zones). Stathmin levels in vivo were assessed by immunohistochemistry. To assess the effects of agents that modulate proliferation and differentiation, RC and GC chondrocytes were cultured in the presence of 10⁻¹⁰ to 10⁻⁸ M 1α,25-(OH)₂D₃, which regulates proliferation in both cell types but affects differentiation of only GC cells, or 10⁻⁹ to 10⁻⁷ M 24R,25-(OH)₂D₃, which regulates differentiation and maturation of RC cells, but decreases proliferation of GC cells. In addition, RC cells were treated with 0.44 or 0.88 ng/mL of recombinant human transforming growth factor β1 (rhTGF-β1), which stimulates proliferation of RC cells and regulates proteoglycan production, but not alkaline phosphatase activity. Stathmin protein levels were determined using quantitative immunoblots, with recombinant human stathmin as a standard. The results show that stathmin levels are associated with proliferation. Proliferating chondrocytes in vivo exhibited higher levels of immunoreactive stathmin than either RC or GC cells in the growth plate. In culture, 1α,25-(OH)₂D₃ caused a dose-dependent de-crease in stathmin in RC and GC cells within 24 h. 24 R, 25-(OH)₂D₃ also reduced stathmin levels in GC cells within 24 h but only affected RC cells after prolonged exposures (96 h), at which time RC cells express a GC-like phenotype. rhTGF-β1 caused an increase in stathmin levels in RC cells. Stathmin levels are sensitive to protein kinase C (PKC) in other cells. Inhibition of PKC with chelerythrine had no effect on the response of RC cells to 1α,25-(OH)₂D₃ but it blocked the effect of rhTGF-β1, indicating that decreases in stathmin by vitamin D₃ metabolites may not be modulated by PKC, whereas increases in stathmin via rhTGF-β1 may be regulated via a PKC-dependent mechanism. These results support the hypothesis that constitutively expressed levels of stathmin are related to cell maturation state and that they are modulated by factors that regulate proliferation.     

microRNAs与胰腺癌的研究进展

胰腺癌是恶性程度较高的肿瘤,早期诊断困难。microRNAs（miRNAs）由19～23个核苷酸所组成的小分子单链RNA。miRNAs属基因负调控因子,可在转录后水平调控靶基因的表达,从而影响肿瘤细胞的发育、分化和凋亡等。近年研究发现,胰腺癌组织、细胞株、癌前病变和血浆中均存在miRNAs表达谱异常,提示miRNAs可能在胰腺癌发生和发展机制的研究、诊断、治疗和预后判断中具有一定应用价值。本文就相关研究进展作一综述。     

Frat1与β-catenin在非小细胞肺癌中表达的相关性及意义

目的探讨Frat1在肺癌组织中的表达情况以及Frat1与β-catenin在肺癌组织中表达的相关性。方法用免疫组化SP法对115例原发性非小细胞肺癌(NSCLC)患者手术标本中Frat1和β-catenin的表达进行检测,使用SPSS16.0统计软件进行分析。结果在NSCLC中,Frat1的表达与肺癌组织的低分化(P=0.035)、淋巴结转移(P=0.019)、TNM分期相关(P=0.010);β-catenin的表达与肺癌组织的低分化(P=0.017)、淋巴结转移(P=0.007)、TNM分期相关(P=0.016);Frat1的表达与β-catenin的表达有相关性(P=0.003)。结论 Frat1和β-catenin与肺癌的低分化、转移、高级别TNM分期等恶性表型有关,二者在肺癌组织中的表达有相关性,Frat1可能成为NSCLC患者靶向治疗的新靶点。     

Cardiac and skeletal myopathy in beta myosin heavy-chain simian virus 40 tsA58 transgenic mice.

The mechanisms regulating cardiac muscle differentiation and development are incompletely understood. To examine the relationships between cardiocyte proliferation and differentiation, we tested the ability of a fragment from the rat beta myosin heavy-chain (MHC beta) gene to correctly target expression of a thermolabile simian virus 40 large tumor antigen allele (tsA58) in the developing mouse. Transgene expression in the heart was observed as early as 10 days postconception and was developmentally regulated in parallel with the endogenous MHC beta gene. Expression was also detected in developing skeletal muscle, although at low levels. Despite the temperature sensitivity of the mutant large tumor antigen protein, a subset of transgenic mice in several lineages developed marked cardiac and skeletal myopathies.     

Neuroendocrine differentiation:The mysterious fellow of colorectal cancer

Neuroendocrine differentiation in sporadic colorectal cancer has been recognized since decades, but its clinical impact is still controversially discussed. Detailed parameter analyses hint at the possibility that probablynot neuroendocrine differentiation itself, but its association with poor grade of tumor differentiation, lymph node metastases, distant metastases and other unfavorable features contribute to worse clinical outcome. However, other studies deny a relationship between neuroendocrine differentiation and prognosis of colorectal cancer. This review elucidates, whether new insights into the origin of neuroendocrine differentiation in the intestinal epithelium, its regulation by m TOR pathway components and its possible link to the intestinal stem cell compartment could determine a role of neuroendocrine cells as prognostic marker and putative therapeutic target in sporadic colorectal cancer.