胃癌中Fascin基因的表达及与进展期胃癌预后相关的蛋白质组学研究
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摘要
第一部分Fascin基因在胃癌中的表达及其意义
【目的】Fascin蛋白代表一类肌动蛋白结合蛋白家族,其蛋白质编码的产物是一种细胞骨架蛋白。这种蛋白可以与F-肌动蛋白相结合,定位于细胞质张力纤维和细胞膜皱褶(ruffles)边缘的丝状伪足、微棘(microspikes)等细胞突起的核心肌动蛋白束,通过与F-肌动蛋白的结合,可以完成细胞的附着和运动。这种结构的形成受细胞细胞外基质和细胞内信号的调控。研究发现,在正常人上皮细胞中,在食道鳞状上皮基底层和表皮基底层中均有表达,而在其他的上皮组织没有表达。在对于肿瘤组织上皮研究中发现,在多种癌症上皮细胞中,Fascin呈阳性表达,且在部分肿瘤中与肿瘤的预后有一定关系。在对于Fascin在消化道肿瘤中表达的研究,目前报道较少。本实验通过免疫组化方法研究Fascin蛋白在249例胃癌病人肿瘤细胞中的表达,结合肿瘤病人的临床病理学特征,综合分析不同类型肿瘤细胞的临床病理特征与Fascin表达之间的关系,以期发现Fascin在胃癌中的表达及与预后的关系。
【研究方法】采用免疫组织化学方法对北京大学临床肿瘤医院自1996～2001年间手术切除的胃癌手术标本249例行Fascin免疫组化染色,研究Fascin在胃癌病人的表达。同时收集这些病例的临床资料,包括病人的年龄、性别、胃癌的分期、肿瘤的TNM分期、肿瘤细胞的分化。对病人的术后生存进行随访观察。通过统计学软件SSPS 13.0,分析所得到的临床病理数据和Fascin的表达水平的关系。
【结果】249例病人中,55例病人肿瘤细胞呈阳性表达(22.1%),其中37例表达为“1+”(14.9%),18例病人肿瘤细胞表达为“2+”(7.2%)。通过对Fascin的表达与临床病理学资料的研究,我们发现Fascin的表达与病人的年龄(p=0.032)、胃癌细胞的分化程度相关,其中,在高分化的胃癌肿瘤细胞中,Fascin的表达与低分化的肿瘤细胞相比较有显著性差异(p=0.001)。而在性别、肿瘤的T、N、M分期方面,Fascin的表达无明显差异。另外,我们发现,在Fascin表达呈强阳性(2+)的病人中,其预后要明显差于阴性表达的病人。
【结论】1.Fascin在正常胃腺上皮中无表达,在胃癌中有表达,胃癌中Fascin的表达,提示胃癌细胞的运动骨架发生改变。
2.Fascin在分化不同的胃癌中表达有差异,提示胃癌的分化与其表达强度不同与存在一定关系。
3.Fascin在胃癌病人中的高表达提示预后不良。
第二部分与进展期胃癌预后相关的蛋白组学研究
【研究目的】胃癌是危害我国人类健康的常见恶性肿瘤,具有较高的发病率和死亡率,严重威胁人类的生命和健康。虽然早期胃癌治疗目前的五年生存率可以达到85%以上,但在我国这部分病人的比例仅仅占到10%-30%。在就诊的胃癌病例中,绝大部分为进展期胃癌,其整体治疗效果不好,预后差异较大。因此术前通过寻找合适的肿瘤标志物,对于术前准确的病理分期(TNM)、提供针对性措施的治疗、判断进展期胃癌病人的预后等方面有深远的意义。
肿瘤标志物,是恶性肿瘤发生和增殖过程中,由肿瘤细胞的基因表达而合成、分泌的,或因机体对肿瘤反应而异常产生的、反应肿瘤存在和生长的一类物质,是检测、诊断、治疗、监测肿瘤和判断肿瘤预后的重要标志。目前临床上常用的胃癌肿瘤标志物有CEA,CA19-9等,由于缺乏一定的特异性和敏感性,主要用于胃癌病人的初筛和治疗后的复发监测。目前临床工作中,缺少反映进展期胃癌预后相关的肿瘤标志物。
蛋白组学(protemics)是以蛋白质组为研究对象,分析细胞内动态变化蛋白质的组成成份、表达水平与修饰状态,了解蛋白质之间的相互作用与联系,在整体水平上研究蛋白质的组成与调控的活动规律。同时质谱技术的飞速发展和二维电泳技术的不断进步,为蛋白质组研究进行高灵敏度、高速鉴定提供了有力支持,为分析体液中各种复杂蛋白质成分提供了可能。用蛋白质组学来研究肿瘤,有利于筛选肿瘤标志蛋白,判断肿瘤的预后,确定肿瘤治疗靶标,寻找新的肿瘤特异抗原。
通过蛋白质组学技术研究不同预后的进展期胃癌病人之间蛋白表达的差异,可以帮助我们发现一系列的反应不同预后的进展期胃癌病人的蛋白表达,通过这些蛋白质的筛选和进一步研究,以期发现能够反应进展期胃癌病人预后的肿瘤标志物,通过这些标志物,可以对胃癌的分期做出准确判断,可以推测胃癌病人的预后,以及寻找胃癌药物靶向治疗的新思路。
【研究方法】为了鉴定与进展期胃癌患者预后相关的蛋白,我们回顾性选取了预后相差较大的两组进展期胃癌患者的冰冻组织为研究对象(预后好的一组患者的生存期均＞34个月,预后差一组患者的生存期均＜15个月)。分别提取两组的组织蛋白经等量混合、胰酶消化过夜后,应用NanoLC-MS/MS(LTQ)(纳升级液相色谱串联质谱,线性离子阱)方法得到两组差异蛋白的氨基酸序列,数据经Mascot服务器及Swiss-prot、NCBI非冗余蛋白质数据库进行了常规序列相似性分析及蛋白的鉴定。
针对两组间表达差异较大的基因S100P和HnRNP A2/B1,我们采用了免疫组化方法对93例进展期胃癌病人的标本进行了检测,同时采用统计学方法对其在胃癌中的表达与临床病理参数及患者预后的关系进行了分析。
【研究结果】应用蛋白质组的方法,在预后好的组中共鉴别出284个蛋白,在预后差的组中鉴别出213个蛋白,其中,130个蛋白只在预后好的一组被识别,58个蛋白只在预后差的一组被识别。其中在两组间均鉴别出且差异大于3倍的有14个,大于两倍的有28个。对于两组中分别鉴别出的蛋白,应用WEGO在线工具,对其基因功能进行了分类,这些蛋白涉及钙离子的信号传导、细胞代谢、应激反应、细胞骨架蛋白等等,为进一步寻找可以预测进展期胃癌预后的肿瘤标志物奠定了基础。这些蛋白中,有些已经被文献证实与胃癌的预后或转移等相关。
通过对16例预后不同的进展期胃癌病人的临床病理学资料进行分析,我们发现,在不同预后的进展期胃癌病人中,发生淋巴结转移在N1和超过N1转移的两组中,其差异具有显著性。我们期望通过差异蛋白组学的研究,筛选出能够预测进展期胃癌病人淋巴结转移状态的肿瘤标志物,针对两组间表达差异较大的基因S100P和HnRNP A2/B1,我们采用了免疫组化方法进行了检测,同时对其在胃癌中的表达与临床病理参数及患者预后的关系进行了描述,结果发现,S100P在正常胃粘膜中表达较高,在胃癌中的表达下降,在本组的93例病例中其阳性表达率为47.3%,并且其在胃癌中的高表达与患者的预后相关(P=0.0375),S100P在胃癌中的高表达与原发肿瘤的浸润深度和淋巴结转移状态相关(P=0.006,P=0.006)。研究表明,免疫组化和蛋白质组学的分析鉴定结果是一致的,S100P可以用来作为判断进展期胃癌的淋巴结转移和预后的肿瘤标志物。而在HnRNPA2/B1的免疫组化中发现,其在胃癌组织中的表达为92.6%,而在癌旁的非肿瘤组织中,也发现了其阳性表达,统计学分析,HnRNP A2/B1的表达与病人的临床病理学资料中差异无显著性意义,表明其并不适合作为判断进展期胃癌预后的肿瘤标志物。
【结论】
1.应用蛋白质组学研究技术,可以在不同预后的进展期胃癌病人筛选出差异表达的蛋白,这些蛋白涉及钙离子的信号传导、细胞代谢、应激反应、细胞骨架蛋白等等,可以为鉴定胃癌病人的分期、预后相关的肿瘤标志物研究提供基础。
2.淋巴结转移状态(超过第一站的淋巴结转移)是影响进展期胃癌病人预后的一个关键因素。
3.S100P可以反应进展期胃癌病人的淋巴结转移状态,从而可以作为肿瘤标志物用来判断进展期胃癌病人的预后。
4.HnRNP A2/B1不适合用于判断进展期胃癌预后的肿瘤标志物。
5.进展期胃癌的蛋白质组学研究中筛选的蛋白质还需要进行进一步的验证。
Objective:Fascin,a structurally unique actin cross-linking protein,which functions in the organization of two major forms of actin-based strctures:cell protrusions and cytoplasmic microfilament bundles.Cell protrusions include filopodia,spikes, microvilli and dendrites of dendritic cells,which have roles in cell-matrix adhesion, cell interactions and cell migration.While cytoplasmic bundles participate in the formation of cell architecture.Recent data showed that fascin is up-regualted in some epithelial carcinomas and correlates with the poor survival.But the expression of fascin in the gastric carcinoma is still not known much.Methods:Paraffin sections of gastric carcinoma of 249 patients were investigated by immunohistochemistry with monoclonal antifascin antibody,those that were stained more than 5%of tumor cells were recorded as positive immuno reactivity.
Results:In 249 patients,55 were found positive fascin immunoreactivity(22.1%),37 were classified "1+"(14.9%),and 18 of the patients were classified "2+"(7.2%). Furthermore,with investigating the relationships between fascin expression and clinicopathological characteristics,we found the expression of fascin correlated with the patient ages(p=0.032),and the differentiation degree of the gastric carcinoma.The expression of fascin was significantly higher in well differentiated carcinoma than those in poorly-differentiated group(p=0.001).while no correlations were found between the sex,T stage,N stage,M stage and the tumor location).Those patients with no fascin expression seemed to have a better prognosis than those patients with fascin(2+) expression.
Conclusion:1.There is no expression of fascin in normal stomach epithelium,but there is fascin expression in gastric cancer,which indicated that the change of skeleton of gastric carcinoma ceils.
2.There are different fascin expression in different differentiated gastric carcinoma. Which indicated that the expression of fascin is correlated with the tumor differentiation.
3.Those patients with fascin expression may have a poor prognosis.
[Objective]Gastric cancer is one of the main malignant tumors in our country,and it has certain morbility and mortility.Although the 5-year survival rate of early stage gastric cancer can proceed about 85%,but the number of these patitent is just only 10% to 30%.Most of the patients with gastrc cancer are found to be late stage,so the prognosis of these patients are poor,and different from each other.So,it is important to find some markers to staging the tumor stage correctly,and to judge the real prognosis of the advanced gastric cancer.
A tumor marker is a substance found in the blood,urine,or body tissues that can be elevated in cancer,among other tissue types.It can be produced by the tumor cell or by the reaction of the body,it can relect the existence and the growth of the tumor.Tumor marker can be used as the detection,diagnosis,treatment,surveillance and the judgement of the prognosis.CEA and CA19-9 are the markers used now in clinic. Because of the low sensitivity and specificity,these markers are mostly be used as the prescreening and the surveillance for the patients with gastric cancers.The use of these tumor marekers are limited in the judgement of the prognosis of the patients with gastric cancers.There are still no tumor markers that could be used to judge the prognosis of the advanced gastric cancer.
Proteomics,a newly technique used to analysis the cellular protein composition, expression and modification,is very useful for identifying disease-associated proteins that show changes in expression and modification corresponding to a disease condition. And with rapid development of technique of Mass Spectrum and 2-DE,it si possible to find out some tumor-realted proteins as the tumor mareker to judge the stage and the prognosis of the patients with gastric cancer.These tumor-related proteins are expected to be biomarkers for diagnosis and putative targeted proteins for treatment
[Methods]In the study,to identify the prognosis related proteins of advanced gastric cancer with different prognosis,we selected two groups of cancer tissues from stage Ⅲ～Ⅳgastric cancer patients with very different survival time for study(For good survival group,the average survival time is＞34 months,and for poor survival group, the average survival time is＜15 months.) Nanoflow liquid chromatography system interfaced with a liner ion trap LTQ mass spectrometer was used and database searches were done against NCBI non-redundant database and SWISS-PROT database on an in-house Mascot server and the identified proteins were classified through an online "Web Gene Ontology Annotation Plot" tool.With so many different proteins,we choose two obviously different proteins S100P and HnRNP A2/B1.With the method of Immunohistochemistry,we detect the expression of S100P and HnRNP A2/B1 in 93 patients with advanced gastric cancer.Furthermore,we also analyse the result with the clinicopathological parameters with SPSS 13.0.
[Results]With the method of proteomics,There were 284 and 213 proteins identified for group G and group P Prespectively.Among those,130 proteins were detected exclusively in group G and 58 proteins exclusively in group P.There were 14 proteins whose fold change is more than 3 times and 28 proteins whose fold change is more than 2 times.These protein markers function in calcium ion signaling pathway,cellular metabolism,cytoskeleton formation,stress reaction,etc.We found that in these two groups,the difference lies in numbers but not categories and several of these proteins were verified to be related with prognosis or the metastasis of gastric cancer patients.
With the statitic analysis of the two group of advanced gastric cancer with different prognosis.We found that the status of metastatic(＜N1 vs＞N1) lymph node is predominant in the prognosis of advanced gastric cancer.So we detect two different protein S100P and HnRNP A2/B1.We found the expression of S100P is about 47.3,and the expression is closely related with prognosis P=0.0375),also the expression is related with the depth of tumor invasion and the status of lymph node metastasis(＜N1 vs＞N1)(P = 0.006,P = 0.006).While the expression of HnRNP A2/B1 is about 92.6%.and there is no significant with the expression and teh prognosis.Furthermore, we also detect the expression of HnRNP A2/B1 in the paratumor tissue.
[Conclusion]
1.With the method of nanoflow liquid chromatography tandem mass spectrometric approach,we can select the different expressed-protein in the advanced gastric cancer patients with different prognosis.These protein markers function in calcium ion signaling pathway,cellular metabolism,cytoskeleton formation,stress reaction,etc. These can be provide the basis of tumor markers to judge the stage and the prognosis.
2.The status of lymph metastasis(lymph node exceed the N1) is a key factor to jude the prognosis of advanced gastric cancer.
3.S100P can reflect the status of lymph nodes in patients with advanced gastric cancer.So it can be a tumor marker to judge the prognosis for patients with advanced gastric cancer.
4.HnRNP A2/B1 is not a ideal marekr to judge the prognosis for patients with advanced gastric cancer.
5.The proteins selected by proteomics to reflect the prognosis need to be verified further.
In all,the nanoflow liquid chromatography tandem mass spectrometric approach is efficient in identifying differentially expressed proteins.With the identification of some protein selected,we know that the method is relaible and need to be further verified.Using proteomic method,several prognosis-related proteins were identified and it provide a basis for the further reasearch.
【目的】Fascin蛋白代表一类肌动蛋白结合蛋白家族,其蛋白质编码的产物是一种细胞骨架蛋白。这种蛋白可以与F-肌动蛋白相结合,定位于细胞质张力纤维和细胞膜皱褶(ruffles)边缘的丝状伪足、微棘(microspikes)等细胞突起的核心肌动蛋白束,通过与F-肌动蛋白的结合,可以完成细胞的附着和运动。这种结构的形成受细胞细胞外基质和细胞内信号的调控。研究发现,在正常人上皮细胞中,在食道鳞状上皮基底层和表皮基底层中均有表达,而在其他的上皮组织没有表达。在对于肿瘤组织上皮研究中发现,在多种癌症上皮细胞中,Fascin呈阳性表达,且在部分肿瘤中与肿瘤的预后有一定关系。在对于Fascin在消化道肿瘤中表达的研究,目前报道较少。本实验通过免疫组化方法研究Fascin蛋白在249例胃癌病人肿瘤细胞中的表达,结合肿瘤病人的临床病理学特征,综合分析不同类型肿瘤细胞的临床病理特征与Fascin表达之间的关系,以期发现Fascin在胃癌中的表达及与预后的关系。
【研究方法】采用免疫组织化学方法对北京大学临床肿瘤医院自1996～2001年间手术切除的胃癌手术标本249例行Fascin免疫组化染色,研究Fascin在胃癌病人的表达。同时收集这些病例的临床资料,包括病人的年龄、性别、胃癌的分期、肿瘤的TNM分期、肿瘤细胞的分化。对病人的术后生存进行随访观察。通过统计学软件SSPS 13.0,分析所得到的临床病理数据和Fascin的表达水平的关系。
【结果】249例病人中,55例病人肿瘤细胞呈阳性表达(22.1%),其中37例表达为“1+”(14.9%),18例病人肿瘤细胞表达为“2+”(7.2%)。通过对Fascin的表达与临床病理学资料的研究,我们发现Fascin的表达与病人的年龄(p=0.032)、胃癌细胞的分化程度相关,其中,在高分化的胃癌肿瘤细胞中,Fascin的表达与低分化的肿瘤细胞相比较有显著性差异(p=0.001)。而在性别、肿瘤的T、N、M分期方面,Fascin的表达无明显差异。另外,我们发现,在Fascin表达呈强阳性(2+)的病人中,其预后要明显差于阴性表达的病人。
【结论】1.Fascin在正常胃腺上皮中无表达,在胃癌中有表达,胃癌中Fascin的表达,提示胃癌细胞的运动骨架发生改变。
2.Fascin在分化不同的胃癌中表达有差异,提示胃癌的分化与其表达强度不同与存在一定关系。
3.Fascin在胃癌病人中的高表达提示预后不良。
第二部分与进展期胃癌预后相关的蛋白组学研究
【研究目的】胃癌是危害我国人类健康的常见恶性肿瘤,具有较高的发病率和死亡率,严重威胁人类的生命和健康。虽然早期胃癌治疗目前的五年生存率可以达到85%以上,但在我国这部分病人的比例仅仅占到10%-30%。在就诊的胃癌病例中,绝大部分为进展期胃癌,其整体治疗效果不好,预后差异较大。因此术前通过寻找合适的肿瘤标志物,对于术前准确的病理分期(TNM)、提供针对性措施的治疗、判断进展期胃癌病人的预后等方面有深远的意义。
肿瘤标志物,是恶性肿瘤发生和增殖过程中,由肿瘤细胞的基因表达而合成、分泌的,或因机体对肿瘤反应而异常产生的、反应肿瘤存在和生长的一类物质,是检测、诊断、治疗、监测肿瘤和判断肿瘤预后的重要标志。目前临床上常用的胃癌肿瘤标志物有CEA,CA19-9等,由于缺乏一定的特异性和敏感性,主要用于胃癌病人的初筛和治疗后的复发监测。目前临床工作中,缺少反映进展期胃癌预后相关的肿瘤标志物。
蛋白组学(protemics)是以蛋白质组为研究对象,分析细胞内动态变化蛋白质的组成成份、表达水平与修饰状态,了解蛋白质之间的相互作用与联系,在整体水平上研究蛋白质的组成与调控的活动规律。同时质谱技术的飞速发展和二维电泳技术的不断进步,为蛋白质组研究进行高灵敏度、高速鉴定提供了有力支持,为分析体液中各种复杂蛋白质成分提供了可能。用蛋白质组学来研究肿瘤,有利于筛选肿瘤标志蛋白,判断肿瘤的预后,确定肿瘤治疗靶标,寻找新的肿瘤特异抗原。
通过蛋白质组学技术研究不同预后的进展期胃癌病人之间蛋白表达的差异,可以帮助我们发现一系列的反应不同预后的进展期胃癌病人的蛋白表达,通过这些蛋白质的筛选和进一步研究,以期发现能够反应进展期胃癌病人预后的肿瘤标志物,通过这些标志物,可以对胃癌的分期做出准确判断,可以推测胃癌病人的预后,以及寻找胃癌药物靶向治疗的新思路。
【研究方法】为了鉴定与进展期胃癌患者预后相关的蛋白,我们回顾性选取了预后相差较大的两组进展期胃癌患者的冰冻组织为研究对象(预后好的一组患者的生存期均＞34个月,预后差一组患者的生存期均＜15个月)。分别提取两组的组织蛋白经等量混合、胰酶消化过夜后,应用NanoLC-MS/MS(LTQ)(纳升级液相色谱串联质谱,线性离子阱)方法得到两组差异蛋白的氨基酸序列,数据经Mascot服务器及Swiss-prot、NCBI非冗余蛋白质数据库进行了常规序列相似性分析及蛋白的鉴定。
针对两组间表达差异较大的基因S100P和HnRNP A2/B1,我们采用了免疫组化方法对93例进展期胃癌病人的标本进行了检测,同时采用统计学方法对其在胃癌中的表达与临床病理参数及患者预后的关系进行了分析。
【研究结果】应用蛋白质组的方法,在预后好的组中共鉴别出284个蛋白,在预后差的组中鉴别出213个蛋白,其中,130个蛋白只在预后好的一组被识别,58个蛋白只在预后差的一组被识别。其中在两组间均鉴别出且差异大于3倍的有14个,大于两倍的有28个。对于两组中分别鉴别出的蛋白,应用WEGO在线工具,对其基因功能进行了分类,这些蛋白涉及钙离子的信号传导、细胞代谢、应激反应、细胞骨架蛋白等等,为进一步寻找可以预测进展期胃癌预后的肿瘤标志物奠定了基础。这些蛋白中,有些已经被文献证实与胃癌的预后或转移等相关。
通过对16例预后不同的进展期胃癌病人的临床病理学资料进行分析,我们发现,在不同预后的进展期胃癌病人中,发生淋巴结转移在N1和超过N1转移的两组中,其差异具有显著性。我们期望通过差异蛋白组学的研究,筛选出能够预测进展期胃癌病人淋巴结转移状态的肿瘤标志物,针对两组间表达差异较大的基因S100P和HnRNP A2/B1,我们采用了免疫组化方法进行了检测,同时对其在胃癌中的表达与临床病理参数及患者预后的关系进行了描述,结果发现,S100P在正常胃粘膜中表达较高,在胃癌中的表达下降,在本组的93例病例中其阳性表达率为47.3%,并且其在胃癌中的高表达与患者的预后相关(P=0.0375),S100P在胃癌中的高表达与原发肿瘤的浸润深度和淋巴结转移状态相关(P=0.006,P=0.006)。研究表明,免疫组化和蛋白质组学的分析鉴定结果是一致的,S100P可以用来作为判断进展期胃癌的淋巴结转移和预后的肿瘤标志物。而在HnRNPA2/B1的免疫组化中发现,其在胃癌组织中的表达为92.6%,而在癌旁的非肿瘤组织中,也发现了其阳性表达,统计学分析,HnRNP A2/B1的表达与病人的临床病理学资料中差异无显著性意义,表明其并不适合作为判断进展期胃癌预后的肿瘤标志物。
【结论】
1.应用蛋白质组学研究技术,可以在不同预后的进展期胃癌病人筛选出差异表达的蛋白,这些蛋白涉及钙离子的信号传导、细胞代谢、应激反应、细胞骨架蛋白等等,可以为鉴定胃癌病人的分期、预后相关的肿瘤标志物研究提供基础。
2.淋巴结转移状态(超过第一站的淋巴结转移)是影响进展期胃癌病人预后的一个关键因素。
3.S100P可以反应进展期胃癌病人的淋巴结转移状态,从而可以作为肿瘤标志物用来判断进展期胃癌病人的预后。
4.HnRNP A2/B1不适合用于判断进展期胃癌预后的肿瘤标志物。
5.进展期胃癌的蛋白质组学研究中筛选的蛋白质还需要进行进一步的验证。
Objective:Fascin,a structurally unique actin cross-linking protein,which functions in the organization of two major forms of actin-based strctures:cell protrusions and cytoplasmic microfilament bundles.Cell protrusions include filopodia,spikes, microvilli and dendrites of dendritic cells,which have roles in cell-matrix adhesion, cell interactions and cell migration.While cytoplasmic bundles participate in the formation of cell architecture.Recent data showed that fascin is up-regualted in some epithelial carcinomas and correlates with the poor survival.But the expression of fascin in the gastric carcinoma is still not known much.Methods:Paraffin sections of gastric carcinoma of 249 patients were investigated by immunohistochemistry with monoclonal antifascin antibody,those that were stained more than 5%of tumor cells were recorded as positive immuno reactivity.
Results:In 249 patients,55 were found positive fascin immunoreactivity(22.1%),37 were classified "1+"(14.9%),and 18 of the patients were classified "2+"(7.2%). Furthermore,with investigating the relationships between fascin expression and clinicopathological characteristics,we found the expression of fascin correlated with the patient ages(p=0.032),and the differentiation degree of the gastric carcinoma.The expression of fascin was significantly higher in well differentiated carcinoma than those in poorly-differentiated group(p=0.001).while no correlations were found between the sex,T stage,N stage,M stage and the tumor location).Those patients with no fascin expression seemed to have a better prognosis than those patients with fascin(2+) expression.
Conclusion:1.There is no expression of fascin in normal stomach epithelium,but there is fascin expression in gastric cancer,which indicated that the change of skeleton of gastric carcinoma ceils.
2.There are different fascin expression in different differentiated gastric carcinoma. Which indicated that the expression of fascin is correlated with the tumor differentiation.
3.Those patients with fascin expression may have a poor prognosis.
[Objective]Gastric cancer is one of the main malignant tumors in our country,and it has certain morbility and mortility.Although the 5-year survival rate of early stage gastric cancer can proceed about 85%,but the number of these patitent is just only 10% to 30%.Most of the patients with gastrc cancer are found to be late stage,so the prognosis of these patients are poor,and different from each other.So,it is important to find some markers to staging the tumor stage correctly,and to judge the real prognosis of the advanced gastric cancer.
A tumor marker is a substance found in the blood,urine,or body tissues that can be elevated in cancer,among other tissue types.It can be produced by the tumor cell or by the reaction of the body,it can relect the existence and the growth of the tumor.Tumor marker can be used as the detection,diagnosis,treatment,surveillance and the judgement of the prognosis.CEA and CA19-9 are the markers used now in clinic. Because of the low sensitivity and specificity,these markers are mostly be used as the prescreening and the surveillance for the patients with gastric cancers.The use of these tumor marekers are limited in the judgement of the prognosis of the patients with gastric cancers.There are still no tumor markers that could be used to judge the prognosis of the advanced gastric cancer.
Proteomics,a newly technique used to analysis the cellular protein composition, expression and modification,is very useful for identifying disease-associated proteins that show changes in expression and modification corresponding to a disease condition. And with rapid development of technique of Mass Spectrum and 2-DE,it si possible to find out some tumor-realted proteins as the tumor mareker to judge the stage and the prognosis of the patients with gastric cancer.These tumor-related proteins are expected to be biomarkers for diagnosis and putative targeted proteins for treatment
[Methods]In the study,to identify the prognosis related proteins of advanced gastric cancer with different prognosis,we selected two groups of cancer tissues from stage Ⅲ～Ⅳgastric cancer patients with very different survival time for study(For good survival group,the average survival time is＞34 months,and for poor survival group, the average survival time is＜15 months.) Nanoflow liquid chromatography system interfaced with a liner ion trap LTQ mass spectrometer was used and database searches were done against NCBI non-redundant database and SWISS-PROT database on an in-house Mascot server and the identified proteins were classified through an online "Web Gene Ontology Annotation Plot" tool.With so many different proteins,we choose two obviously different proteins S100P and HnRNP A2/B1.With the method of Immunohistochemistry,we detect the expression of S100P and HnRNP A2/B1 in 93 patients with advanced gastric cancer.Furthermore,we also analyse the result with the clinicopathological parameters with SPSS 13.0.
[Results]With the method of proteomics,There were 284 and 213 proteins identified for group G and group P Prespectively.Among those,130 proteins were detected exclusively in group G and 58 proteins exclusively in group P.There were 14 proteins whose fold change is more than 3 times and 28 proteins whose fold change is more than 2 times.These protein markers function in calcium ion signaling pathway,cellular metabolism,cytoskeleton formation,stress reaction,etc.We found that in these two groups,the difference lies in numbers but not categories and several of these proteins were verified to be related with prognosis or the metastasis of gastric cancer patients.
With the statitic analysis of the two group of advanced gastric cancer with different prognosis.We found that the status of metastatic(＜N1 vs＞N1) lymph node is predominant in the prognosis of advanced gastric cancer.So we detect two different protein S100P and HnRNP A2/B1.We found the expression of S100P is about 47.3,and the expression is closely related with prognosis P=0.0375),also the expression is related with the depth of tumor invasion and the status of lymph node metastasis(＜N1 vs＞N1)(P = 0.006,P = 0.006).While the expression of HnRNP A2/B1 is about 92.6%.and there is no significant with the expression and teh prognosis.Furthermore, we also detect the expression of HnRNP A2/B1 in the paratumor tissue.
[Conclusion]
1.With the method of nanoflow liquid chromatography tandem mass spectrometric approach,we can select the different expressed-protein in the advanced gastric cancer patients with different prognosis.These protein markers function in calcium ion signaling pathway,cellular metabolism,cytoskeleton formation,stress reaction,etc. These can be provide the basis of tumor markers to judge the stage and the prognosis.
2.The status of lymph metastasis(lymph node exceed the N1) is a key factor to jude the prognosis of advanced gastric cancer.
3.S100P can reflect the status of lymph nodes in patients with advanced gastric cancer.So it can be a tumor marker to judge the prognosis for patients with advanced gastric cancer.
4.HnRNP A2/B1 is not a ideal marekr to judge the prognosis for patients with advanced gastric cancer.
5.The proteins selected by proteomics to reflect the prognosis need to be verified further.
In all,the nanoflow liquid chromatography tandem mass spectrometric approach is efficient in identifying differentially expressed proteins.With the identification of some protein selected,we know that the method is relaible and need to be further verified.Using proteomic method,several prognosis-related proteins were identified and it provide a basis for the further reasearch.
引文
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