凋亡调控相关基因FAF1、Bcl-2和Survivin在Hpylori感染胃癌变过程中的表达机制初探及临床意义
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摘要
研究背景及目的幽门螺旋杆菌(Helicobacter pylori,H pylori)感染作为一个明确的致癌因素已得到广泛公认,在Correa提出的由“慢性浅表性胃炎(CSG)-慢性萎缩性胃炎(CAG)-肠上皮化生(IM)-不典型增生(AH)-胃癌(GC)”被公认为人类胃癌,尤其是肠型胃癌发生的典型模式,H pylori被认为是这一发展过程的首要推动因子。胃癌是一种基因病,胃癌的发生发展是多种基因改变逐渐累积的结果,不同的基因可能在不同的阶段发挥作用。在这个复杂的多基因作用过程中,不仅与原癌基因的激活和抑癌基因的突变有关,还与细胞凋亡基因密切相关。在H pylori感染所致癌变过程中,凋亡相关基因在胃癌的发生发展过程中可能起到一个关键性的作用,但目前H pylori感染在胃癌发病中的确切作用及细胞凋亡调控机制及两者之间的相关性尚未阐明,特别是在凋亡调控机制中,凋亡诱导/抑制基因可能在不同阶段发挥不同作用,而它们与H pylori感染所致胃癌变过程中作用的双面性及可能机制更有待探索。Fas相关因子1 ( Fas-associated factor 1,FAF1)是新近发现的Fas死亡信号结合体的成员之一,其N-末端区域能与Fas特异性的结合,它是能够增强Fas介导细胞凋亡的蛋白分子,且在胃癌组织中有特异性低表达,关于FAF1的作用目前知道的尚少,在我们的前期研究中初步证实FAF1在胃癌组织中低表达,作为凋亡诱导因子,与H pylori感染所致胃癌变的相关性及作用机理尚无相关报道。B细胞淋巴瘤/白血病-2(B-cell lymphoma/Leukemia-2,Bcl-2)基因是最早发现的细胞凋亡抑制基因,是迄今研究最深入、最广泛的凋亡调控基因之一。业已证明Bcl-2是最重要的抑制肿瘤细胞凋亡的基因。生存素(Survivin)是IAP家族成员之一,是迄今发现最强的凋亡抑制因子,作用于各凋亡途径的汇集点。Survivin在正常成熟的人体组织中不表达或低表达,而在人类大多数肿瘤组织中均存在阳性高表达,提示它在肿瘤的发生发展中发挥重要作用。关于H pylori感染与胃癌变过程中凋亡抑制基因Bcl-2与Survivin的表达作用机制目前研究也尚不多,且在这个过程中与FAF1如何共同发挥作用也有待探索。因此本研究旨在为阐明胃癌变过程中H pylori感染与这些凋亡调控相关基因FAF1、Bcl-2、Survivin的表达的相关性及可能作用机制,并进一步结合临床相关资料,探讨这些凋亡调控相关基因在胃癌的早期诊断、浸润转移以及预后判断中的作用,以便为胃癌的早期诊断和治疗提供具有参考价值的分子生物学指标。
方法用快速尿素酶法、W-S银染法和美蓝法联合检测62例慢性浅表性胃炎(CSG)、55例慢性萎缩性胃炎(CAG)、52例肠化生(IM)、46例不典型增生(AH)、65例胃癌(GC)组织中H pylori的感染,并采用免疫组化分别检测标本中凋亡调控相关基因FAF1、Bcl-2、Survivin蛋白的表达,脱氧核糖核酸末端转移酶介导的缺口末端标记(TUNEL)检查细胞凋亡水平,分析H pylori感染在胃癌变过程中与FAF1、Bcl-2、Survivin蛋白的表达相关性及与细胞凋亡的关系;进一步采用荧光定量法检测标本中FAF1 mRNA、Bcl-2 mRNA、Survivin mRNA的表达水平,探讨H pylori感染对FAF1、Bcl-2、Survivin基因水平调控的影响;并结合临床病例的病理学特征及随访资料,探讨凋亡调控相关基因FAF1、Bcl-2和Survivin在胃癌的早期诊断、浸润转移以及预后判断中的作用。
结果
第一部分:
1. GC形成中的H pylori感染率本组280例病例中,三种方法联合检测H pylori感染率为53.6%,H pylori感染在CSG→CAG→IM→AH→GC发展过程中随着病变恶性程度的增加而感染率增加,分别为30.6%,49.1%,55.8%,65.2%,69.2%。H pylori感染率CAG、IM、AH和AC组较CSG组均明显升高(p<0.05);GC组H pylori感染率较CAG组升高(p<0.05)。
2. GC形成过程中的FAF1、Bcl-2和Survivin蛋白表达及与细胞凋亡的关系在CSG→CAG→IM→AH→GC发展过程中,FAF1的阳性表达率随病变程度加重而逐渐降低,分别为72.6%,65.5%,63.8%,54.3%,36.8%,AH组较CSG阳性率降低(p<0.05),GC组较CSG、CAG、IM组明显降低(p<0.01);Bcl-2的阳性表达率随病变程度加重而逐渐升高,分别为16.1%,21.8%,32.7%,50.0%,61.5%,其中IM组较CSG组阳性率升高(p<0.05);AH、GC组较CSG、CAG组阳性率明显升高(p<0.01);Survivin蛋白在CSG组织中未见表达,在非癌性病变组织中表达程度较弱,在胃癌组织中表达程度较高,分别为0,9.1%,17.3%,45.7%,63.1%,AH、GC组较CSG、CAG、IM组阳性率明显升高(p<0.01)。
细胞凋亡指数(AI)在CSG、CAG阶段逐渐升高,在AH、GC阶段逐渐降低,CAG、IM组较CSG组AI明显升高(p<0.01);AH、GC组较CSG、CAG、IM组AI明显降低(p<0.01)。
在CSG→CAG→IM→AH→GC发展过程中,FAF1阳性表达者凋亡指数均高于FAF1阴性,且各组均具有统计学意义(p<0.05,p<0.01);CAG、IM、AH、GC组Bcl-2阳性表达者凋亡指数均低于Bcl-2阴性,且在IM、AH及GC组具有统计学意义(p<0.05,p<0.01);CAG、IM、AH、GC组Survivin阳性表达者凋亡指数均低于Survivin阴性,且具有统计学意义(p<0.05)。
在CSG→CAG→IM→AH→GC发展过程中,FAF1的表达与病变恶性程度呈负相关(r=-0.251,p<0.05),Bcl-2、Survivin的表达与病变恶性程度呈正相关(r=0.361,0.535,p均<0.01)。FAF1阳性率与Bcl-2和Survivin阳性率呈负相关(r=-0.958、-0.971,p均<0.05),Bcl-2阳性率与Survivin阳性率呈正相关(r=0.995,p<0.01)。FAF1的阳性率与凋亡指数呈正相关趋势(r=0.738,p>0.05),Bcl-2和Survivin的阳性率与凋亡指数呈负相关趋势(r=-0.748、-0.782,p均>0.05)。
3. GC形成过程中H pylori感染与细胞凋亡的关系在CSG组,H pylori阳性AI高于H pylori阴性,差异有统计学意义(t' =2.055,p<0.05),而在GC组,H pylori阳性AI低于H pylori阴性,差异有统计学意义(t' =2.817,p<0.05),在其余三组之间差别无统计学意义(p>0.05)。
4. GC形成过程中H pylori感染对FAF1、Bcl-2和Survivin蛋白表达的影响H pylori阳性AH、GC组FAF1阳性表达率低于H pylori阴性组,且在GC组具有统计学意义(p<0.05),CSG、CAG和IM组H pylori阳性者FAF1阳性表达率略高于H pylori阴性组,但无统计学意义(p>0.05)。H pylori阳性CSG、CAG、IM、AH、GC组Bcl-2表达阳性率均高于H pylori阴性组,且在GC组具有统计学意义(p<0.05)。H pylori阳性CAG、IM、AH、GC组Survivin表达阳性率均高于H pylori阴性组,且在AH、GC组具有统计学意义(p<0.05)。
第二部分:
1. GC形成过程中FAF1、Bcl-2和Survivin mRNA的表达水平
FAF1mRNA在不同胃黏膜病变组织中均能检测到表达,在GC组mRNA相对表达量较低。Bcl-2mRNA在CSG→CAG→IM→AH→GC中阳性表达率分别为22.6%(14/62),30.9%(17/55),40.4%(21/52),58.7%(27/46),69.2%(45/65)。SurvivinmRNA阳性表达率分别为0,12.7%(7/55),25.0%(13/52),54.3%(25/46),75.4%(49/65)。FAF1mRNA在CSG→CAG→IM→AH→GC表达水平分别为0.136±0.008,0.131±0.009,0.128±0.010,0.094±0.032,0.006±0.003;Bcl-2mRNA表达水平分别为0.095±0.015,0.115±0.012,0.173±0.027,0.224±0.042,0.368±0.036;Survivin mRNA表达水平分别为0,0.068±0.007,0.347±0.060,0.553±0.080,1.646±0.356。可以看到,随着恶变程度的进展,FAF1mRNA的表达量逐渐下降,而Bcl-2和SurvivinmRNA表达阳性率和表达量逐渐上升。三个基因在IM阶段开始有表达差异,在GC组差异最为显著,AH组次之。
2. GC形成过程中FAF1、Bcl-2和Survivin mRNA表达的相关性分析经Spearman Correlations等级相关检验,在CSG→CAG→IM→AH→GC发展过程中,FAF1mRNA的表达与病变恶性程度呈负相关(r=-0.827,p<0.01),Bcl-2、Survivin mRNA表达与病变恶性程度呈正相关(r分别0.945,0.918,p均<0.01)。经Bivariate Correlations分析,CSG→CAG→IM→AH→GC发展过程中,FAF1mRNA表达量与Bcl-2和SurvivinmRNA表达量呈负相关(r分别为-0.911、-0.890,p均<0.01),Bcl-2 mRNA表达量与SurvivinmRNA表达量正相关(r=0.906,p<0.01)。
3. GC形成过程中FAF1、Bcl-2和Survivin三者基因表达和蛋白表达的相关性分析
经Bivariate Correlations分析,在CSG→CAG→IM→AH→GC发展过程中,FAF1基因与蛋白表达呈正相关(r=0.298,p<0.01),Bcl-2基因与蛋白表达呈正相关(r=0.324,p<0.01),Survivin基因与蛋白表达呈正相关(r=0.403,p<0.01),均具有一致性。
4. GC形成过程中FAF1、Bcl-2和Survivin mRNA的表达与H pylori感染状况之间的关系
在CSG和CAG组中,H pylori阳性者FAF1mRNA的表达略高于H pylori阴性,在IM组始这种趋势发生改变,在AH、GC组H pylori阳性FAF1mRNA的表达均明显低于H pylori阴性,差异有统计学意义(p<0.05,p<0.01);Bcl-2 mRNA的表达在IM、AH、GC组H pylori阳性均明显高于H pylori阴性,差异有统计学意义(p<0.05,p<0.01);Survivin mRNA的表达在AH、GC组H pylori阳性均明显高于H pylori阴性,差异有统计学意义(p<0.05)。随着胃黏膜恶变程度的加重,H pylori感染对FAF1mRNA的表达起下调作用,而对Bcl-2mRNA和SurvivinmRNA的表达起上调作用。
第三部分:
1. FAF1、Bcl-2和Survivin蛋白表达与胃癌各临床病理特征的相关性
相关性分析显示,FAF1表达与胃癌患者肿瘤大小、病理组织学分级、肿瘤的浸润程度、有无淋巴结转移、有无远处转移、TNM临床分期密切相关(p<0.01)。Bcl-2表达与肿瘤的浸润程度、有无淋巴结转移、TNM临床分期密切相关(p<0.01)。Survivin表达与组织学分级、肿瘤的浸润程度、TNM临床分期密切相关(p<0.05, p<0.01)。同时,相关性分析显示:胃癌中FAF1表达与Bcl-2和Survivin表达呈负相关(r_s=-0.236,r_s=-0.293,p均<0.01),Bcl-2和Survivin表达呈正相关(r_s=0.210,p<0.05)。
2. FAF1、Bcl-2和Survivin表达和临床病理学特征的预后分析
经单因素分析显示,FAF1、Bcl-2和Survivin的表达、肿瘤的大小、发生部位、肿瘤浸润深度、组织学分级、有无淋巴结转移、有无远处转移、TNM临床分期状况均是影响生存的预后因素,其中FAF1的表达为保护性因素,其它均为危险性因素。多因素分析显示FAF1、Bcl-2和Survivin的表达均不能成为影响患者总生存的独立预后因素。
3. FAF1、Bcl-2和Survivin表达对胃癌根治术患者术后生存的影响
随着FAF1表达程度的增加,中位生存时间延长,而随着Bcl-2和Survivin表达程度的增加,中位生存时间缩短。FAF1三组比较,1年、3年和5年生存率比较均有显著性差异(χ~2=1.029,χ~2=2.302,χ~2=6.218,p均<0.01);Bcl-2四组比较,1年生存率未见差异(χ~2=2.201,p=0.532),3年和5年生存率比较均有显著性差异(χ~2=13.102,χ~2=3.017,p均<0.01);Survivin四组比较,1年、3年和5年生存率比较均有显著性差异(χ2= 36.463,χ2=43.787,χ2= 8.646,p均<0.01)。Log-Rank法生存曲线配对比较,FAF1三组之间均有显著差异(p<0.01,p<0.05),Bcl-2组除“-”与“+”外,其余各组之间均有显著性意义(p<0.01, p<0.05)。Survivin组除“-”与“+”、“+”与“++”外,其余各组之间均有显著性意义(p<0.01,p<0.05)。
结论
1.从蛋白水平和细胞水平分析FAF1、Bcl-2和Survivin三个凋亡相关基因在胃黏膜癌变(CSG→CAG→IM→AH→GC)过程中的变化规律,显示了FAF1表达水平逐渐降低,Bcl-2和Survivin表达水平逐渐升高,相应的由FAF1介导和调控的胃黏膜细胞凋亡诱导作用逐渐减弱,而Bcl-2和Survivin介导的凋亡抑制作用逐渐增强,尤其发展到AH阶段后凋亡过程受到明显阻遏,凋亡指数(AI)明显降低,凋亡失衡而导致了胃癌的发生。
2.从基因水平和蛋白水平研究在胃黏膜癌变过程中的H pylori感染对FAF1、Bcl-2和Survivin的调控作用,显示了H pylori感染下调FAF1mRNA的表达, FAF1蛋白表达水平降低,而上调Bcl-2和SurvivinmRNA的表达, Bcl-2和Survivin蛋白表达水平增高,提示了H pylori感染引起FAF1、Bcl-2和Survivin基因调控失衡可能是胃癌变的机制之一。
3.临床分析显示,FAF1、Bcl-2和Survivin的表达与胃癌的生物学行为及临床病理特征密切相关,对胃癌患者预后有重要影响。FAF1高表达者,中位生存时间延长,生存率提高。Bcl-2和Survivin高表达者,中位生存时间缩短,生存率下降。
Investigated background and objective It was knowned that H pylori infection was a definited carcinogenic agent and the first impulse factor of homo-sapiens gastric carcinogenesis,especially typical intestine type in the process of chronic superficial gastris (CSG)- chronic atrophic gastris(CAG)- intestinal melaplasia(IM)- atypical hyperplasia(AH)- gastric carcinoma(GC) , which had been prefered by Correa.GC was a species of genopathy and its carcinogenesis was the gradually accumulated change of multiple genes those possibly made roles in diaparate phases. It was associated with not only proto- oncogene activation and anti-oncogene mutation ,but also cell apoptosis genes, which intimately participate in the gastric carcinogenesis.Possibly apoptosis related genes make critical roles in the process of gastric cancerization with H pylori infection. At present , it is not yet clarity that the sure effect and the mechanism of cell apoptosis regulation with H pylori infection,also the correlation with them ,and the apoptosis inducing and inhibiting genes maybe make different roles in different phases.So it is necessary to explore the pro- apoptotic and antiapoptotic machanism of them in the process of gastric cancerization with H pylori infection. Fas-associated factor 1 (FAF1)was a protein recently discoved and had been demonstrated to be a component of the death inducing signaling complex (DISC) in Fas-mediated apoptosis, whose N-termial region specificly combinated with Fas to enhance the Fas-mediated apoptosis. FAF1 was down-regulated in gastric cancer tissue specificly. Now it is known little about the role of FAF1,and our early study had tentatively confirmed the prior conclusion,furthermore,no report about the correlation and mechanism of action between H pylori infection and FAF1 as a proapoptotic factor in gastric cancerization. B-cell lymphoma/Leukemia-2(Bcl-2) was a anti- apoptotic gene which was discovered earliestly and investigated deeply and extensively up to now.It was known that Bcl-2 was a most important factor to inhibit the apoptosis of tumor cell. Survivin was a member of inhibitors of apoptosis proteins(IAP) family and a most strongest antiapoptotic factor,which affected on the assemble point of all apoptosis pathway.Survivin expression was negative or low in the normal ripe human tissue,but positive and high in human majority tumor tissue, which to hint it important in carcinogenesis and deve- lopment .The machanism of action yet know little between H pylori infection and Bcl-2 as antiapoptotic factors in gastric cancerization,also together with FAF1 as a proapoptotic factor. In conclusion,in this study we aim to clarity the correlation and possible machanism of action between H pylori infection and those genes related with cell apoptosis regulation, furthermore, combining with clinical correlated information, to explore the effect of those genes on the early diagosis , infiltration ,metastasis and prognosis of gastric cancer .Which to offer some referred molecular biological parameters for the early diagosis and treatment of gastric cancer.
Methods To explore the correlation between H pylori infection and FAF1 ,Bcl-2 and Survivin expression in gastric carcinogenesis,also cell apoptosis,H pyloriinfection was evaluated by Rapid Urease Test ,Methylene blue and Warthin-Starry staining method,and the expression of FAF1 ,Bcl-2 and Survivin were detected by immunohistochemical (IHC) staining ,while the level of cell apoptosis were detected by terminal deoxynucleosides mediated nick end labeling (TUNEL)staining,including 62 cases of chronic superficial gastris (CSG), 55 cases chronic atrophic gastris(CAG),52 cases intestinal melaplasia (IM) ,46 cases atypical hyperplasia(AH),65 cases gastric carcinoma(GC). Furthermore,to explore the correlation between H pylori infection and genes transcription,the expressin level of FAF1 mRNA,Bcl-2 mRNA and Survivin mRNA were detected by Fluorescent Qanlity Real-time polymerase chain reaction.Additionaly,combinating with the pathematology and follow-up data of clinical cases , to explore the effect of those genes on the early diagosis , infiltration ,metastasis and prognosis of gastric cancer.
Results
Chapter I
1. The positive rate of H pylori infection during the course of gastric cancer progression. The positive rate of H pylori infection was 53.6% with three methods combined,and increased with the degree of carcinogenesis of gastric mucosa .The positive rate was 30.6%,49.1%,55.8%,65.2%,69.2%,respectively. The infection rate of H pylori in CAG,IM,AH,GC were higher than that in CSC respectively(p<0.05),and GC were higher than CAG(p<0.05).
2. The correlation between the expression of FAF1,Bcl-2 and Survivin protein and cell apoptosis. The positive rate of FAF1 protein expression decreased with the degree of carcinogenesis of gastric mucosa. The positive rate was 72.6%,65.5%,63.8%,54.3%,36.8% respectively. The positive rate of FAF1 protein expression in AH were lower than that in CSG (p<0.01),and GC were lower than CSG,CAG,IM respectively(p<0.01).While, the positive rate of Bcl-2 and Survivin protein expression increased with the degree of carcino- genesis of gastric mucosa. The positive rate of Bcl-2 expression was 16.1%, 21.8%,32.7%,50.0%,61.5% respectively. The positive rate of Bcl-2 expression in IM was higher than in CSG (p<0.05),and AH and GC were higher than CSG and CAG,respectively(p<0.01).The expression of Survivin was negative in CSG,and weak in non-carcinoma pathological tissue,but strong in gastric cancer tissue. The positive rate of Survivin expression was 0,9.1%,17.3%,45.7%,63.1% respectively. The positive rate of Survivin expression in AH and GC were significant higher than in CSG ,CAG and IM(p<0.01).
The AI increased in the phase of CSG and CAG, while decreased in the phase of AH and GC gradually. The AI in CAG and IM were significant higher than in CSG (p<0.01), while AH and GC were lower than CSG,CAG and IM respectively(p<0.01).
During the course of gastric cancer progression ,the AI with FAF1 positive expression were higher than that with FAF1 negative among all groups(p<0.05, p < 0.01),howerver, the AI of Bcl-2 positive expression were lower than negative ,especially in IM,AH and GC(p<0.05,p<0.01),and the AI of Survivin positive expression were lower than negative in CAG, IM,AH and GC( p<0.05).
During the course of gastric cancer progression, there was negative correlation between FAF1 positive and the degree of carcinogenesis of gastric mucosa(r=-0.251,p<0.05), but there were positive correlation between Bcl-2 and Survivin positive and the degree of carcinogenesis of gastric mucosa (r=0.361, 0.535 respectively, p all<0.01).There were negative correlation between FAF1 positive rate and Bcl-2 and Survivin positive rate(r=-0.958, -0.971 respectively,p all < 0.05),howerver positive colleration was found between Bcl-2 and Survivin postive rate(r=0.995,p<0.01). There was only positive correlation tendency between FAF1 positive rate and AI(r=0.738,p>0.05),while negative correlation tendency between Bcl-2 and Survivin positive rate and AI(r=-0.748,-0.782, p all >0.05).
3. The correlation between H pylori infection and cell apoptosis. We found the AI of H pylori positive was higher than that of H pylori negative in CSG (t' =2.055,p<0.05),while lower in GC (t' =2.817,p<0.05).There were no difference in other groups(p>0.05).
4 . The correlation between H pylori infection and the expression of FAF1,Bcl-2 and Survivin protein. We found the positive rate of FAF1 protein expression with H pylori positive was lower than that of H pylori negative in AH and GC, and there was significant difference in GC(p<0.05). There were no difference in other groups, though the positive rate of FAF1 protein expression with H pylori positive was a little high than that with H pylori negative(p>0.05).The positive rate of Bcl-2 protein expression with H pylori positive was higher than that of H pylori negative in all group,but only there was significant difference in GC(p<0.05). The positive rate of Survivin protein expression with H pylori positive was higher than that of H pylori negative in all group,but only there was significant difference in AH and GC(p<0.05).
Chapter II
1. The expression of FAF1,Bcl-2 and Survivin mRNA during the course of gastric cancer progression. During the course of gastric cancer progression (CSG→CAG→IM→AH→GC),FAF1mRNA expression was detected in different gastric mucosa lesion groups,and the relative quantity in GC was lower. The Bcl-2 mRNA positive rate was 22.6%(14/62),30.9(17/55),40.4%(21/52), 58.7%(27/46),69.2%(45/65) respectively. The Survivin mRNA positive rate was 0,12.7%(7/55),25.0%(13/52),54.3%(25/46),75.4%(49/65)respectively.
The level of FAF1mRNA expression in different groups were0.136±0.008, 0.131±0.009,0.128±0.010,0.094±0.032,0.006±0.003 respectively. Bcl-2 mRNA were 0.095±0.015,0.115±0.012,0.173±0.027,0.224±0.042,0.368±0.036 respectively. SurvivinmRNA were 0, 0.068±0.007, 0.347±0.060, 0.553±0.080, 1.646±0.356.We can conclude FAF1 mRNA decreased gradually with the degree of carcinogenesis of gastric mucosa ,but Bcl-2 mRNA and Survivin increased in the same course. The level of FAF1 mRNA expression were lower in IM,AH and GC than that in CSG(p<0.05,p<0.01),and AH was lower than IM(p<0.01),including GC was lower than IM and AH(p<0.01). The level of Bcl-2 mRNA expression were higher in IM,AH and GC than that in CSG and CAG(p<0.01),and AH was higher than IM(p<0.01),including GC washigher than IM and AH(p<0.01). The level of Survivin mRNA expression were higher in IM,AH and GC than that in CAG(p<0.05, p<0.01),and AH was higher than IM(p<0.05),including GC was higher than IM and AH(p<0.01).The level of three genes expression showed difference in IM firstly, the most significant in GC, Following in AH.
2. The correlation among the level of FAF1mRNA ,Bcl-2 mRNA and Survivin mRNA during the course of gastric cancer progression. During the course of gastric cancer progression, there was negative correlation between the level of FAF1 mRNA expression and the degree of carcinogenesis of gastric mucosa (r=-0.827,p<0.01), but there were positive correlation between the level of Bcl-2 and Survivin mRNA expression and the degree of carcinogenesis of gastric mucosa(r=0.945, 0.918 respectively, p all < 0.01) with Spearman Correlations test .
There were negative correlation between the level of FAF1 mRNA expression and the level of Bcl-2 and Survivin mRNA expression (r=-0.911, -0.890 respectively,p all<0.01),howerver positive colleration was found between Bcl-2 mRNA and Survivin mRNA (r=0.906,p<0.01) with Bivariate Correlations analysis.
3. The correlation between mRNA and protein of FAF1,Bcl-2 and Survivin during the course of gastric cancer progression. During the course of gastric cancer progression ,there were positive correlation between the level of FAF1,Bcl-2 and Survivin mRNA expression and the level of Bcl-2 and Survivin protein expression (r=-0.298, 0.324, 0.403 respectively,p all<0.01),so there were consistency between them respectively.
4. The correlation between H pylori infection and the expression of FAF1,Bcl-2 and Survivin mRNA during the course of gastric cancer progression We found the level of FAF1 mRNA expression with H pylori positive was little higher than that of H pylori negative in CSG and CAG , but this tendency altered in IM, howerever, the level of FAF1 mRNA expression with H pylori positive was lower than that of H pylori negative in AH and GC(p<0.05,p<0.01).The level of Bcl-2 mRNA expression with H pylori positive was higher than that of H pylori negative in IM,AH and GC respectively(p<0.05, p<0.01). The level of Survivin mRNA expression with H pylori positive was higher than that of H pylori negative in IAH and GC respectively(p<0.05). H pylori infection can gradually down-regulated the level of FAF1mRNA expression,but up-regulated the expression of Bcl-2 and SurvivinmRNA expression during the course of gastric cancer progression.
Chapter III
1. The correlation on FAF1,Bcl-2 and Survivin protein expression and clinical pathological characteristics in gastric cancer It was showed that there were close correlations between FAF1 expression and tumor size, Histological grade, Tumor infiltration, nodus lymphaticus metastasis, distance metastasis and TNM clinical stage( p<0.01),and between Bcl-2 expression and tumor infiltration, nodus lymphaticus metastasis, and TNM clinicalStage( p<0.01), meanwhile between Survivin expression and tumor histological grade, Tumor infiltration, and TNM clinical stage(p <0.05, p <0.01).There were negative correlation between the level of FAF1 protein expression and the level of Bcl-2 and Survivin protein expression in gastric cancer (r=-0.236,-0.293, respectively,p all<0.01),howerver positive colleration was found between Bcl-2 protein and Survivin protein (r=0.210,p<0.05) .
2. The prognosis factors investigation on the correlation of FAF1,Bcl-2 and Survivin and clinical pathological characteristics in gastric cancer. Single factor COX risk model assay showed the level of FAF1,Bcl-2 and Survivin expression ,tumor size , anatomic site, tumor infiltration, nodus lymphaticus metastasis, distance metastasis and TNM clinical stage histological grade all were markely correlated with the prognosis of patients with gastric cancer by radical resection.FAF1 expression was protect factor ,and others were risk factors. Independent risk factors analysis showed FAF1,Bcl-2 and Survivin were not indepent risk factors which influenced on the prognosis of patients with gastric cancer radical resection.
3. The correlation on FAF1,Bcl-2 and Survivin expression and survival in gastric cancer by radical resection.The median surviral time was prolonged and surviral rate increased with the degree of FAF1 expression increased, Howerver,with Bcl-2 and Survivin expression increased the median surviral time was shorten and surviral rate decreased. There were signifcant defferences for 1 year, 3 years and 5years surviral rate (χ~2=1.029,χ~2=2.302,χ~2=6.218,respectively, p all <0.01). There were significant differences for 3 years and 5years surviral rate(χ~2=13.102,χ~2=3.017,respectively,pall<0.01) among the Bcl-2 groups.There was significant difference among the Survivin groups (-,+,++,+++)for 1year, 3 years and 5years surviral rate (χ~2=36.463,χ~2=43.787,χ~2=8.646,respectively, pall<0.01).With Log-Rank methods,there were significant difference among the different degree three groups of FAF1.Besides Bcl-2(- and+) groups,there were significant difference in other Bcl-2 groups(p<0.01, p<0.05). Besides survivin(- and +,+and ++) groups, there were significant difference in other survivin groups(p<0.01, p<0.05).
Conclusion
1. In this study on the protein and cell fields ,we noticed the FAF1,Bcl-2 and Survivin related apoptosis regulation genes expression level altered obviously in the process of CSG→CAG→IM→AH→GC,with FAF1 expression increased and Bcl-2 and Survivin decreased, which showed proapoptosis factor FAF1 mediated and regulated cell apopotosis attenuated, while anti- proapoptosis factors Bcl-2 and Survivin mediated cell apoptosis to enhance , especially in AH the apoptosis process was repressed obviously ,with AI decreasing the same time, so the disbalance between cell proliferation and apopotosis to induce gastric carcinogenesis.
2.In this study on the gene and protein fields ,we explored the relationship between H pylori infection and FAF1,Bcl-2 and Survivin,and found H pylori infection could down-regulated the level of FAF1 gene and portein expression, but up-regulated the expression of Bcl-2 and Survivin genes and proteins expression in the process of CSG→CAG→IM→AH→GC ,which all showed the disblance between the FAF1 and Bcl-2,Survivin possibly was a mechanism of gastric carcinogenesis induced by H pylori infection.
3. In our clinical study, we found FAF1,Bcl-2 and Survivin all were intimately correlated with the biological behaviour of gastric cancer and clinical pathology characteristic, also were factors which influenced on the surviral prognosis of patients with gastric cancer radical resection. he higer FAF1 protein level was correlated with good prognosis,and higer Bcl-2 and Survivin protein level were correlated with poor prognosis.
方法用快速尿素酶法、W-S银染法和美蓝法联合检测62例慢性浅表性胃炎(CSG)、55例慢性萎缩性胃炎(CAG)、52例肠化生(IM)、46例不典型增生(AH)、65例胃癌(GC)组织中H pylori的感染,并采用免疫组化分别检测标本中凋亡调控相关基因FAF1、Bcl-2、Survivin蛋白的表达,脱氧核糖核酸末端转移酶介导的缺口末端标记(TUNEL)检查细胞凋亡水平,分析H pylori感染在胃癌变过程中与FAF1、Bcl-2、Survivin蛋白的表达相关性及与细胞凋亡的关系;进一步采用荧光定量法检测标本中FAF1 mRNA、Bcl-2 mRNA、Survivin mRNA的表达水平,探讨H pylori感染对FAF1、Bcl-2、Survivin基因水平调控的影响;并结合临床病例的病理学特征及随访资料,探讨凋亡调控相关基因FAF1、Bcl-2和Survivin在胃癌的早期诊断、浸润转移以及预后判断中的作用。
结果
第一部分:
1. GC形成中的H pylori感染率本组280例病例中,三种方法联合检测H pylori感染率为53.6%,H pylori感染在CSG→CAG→IM→AH→GC发展过程中随着病变恶性程度的增加而感染率增加,分别为30.6%,49.1%,55.8%,65.2%,69.2%。H pylori感染率CAG、IM、AH和AC组较CSG组均明显升高(p<0.05);GC组H pylori感染率较CAG组升高(p<0.05)。
2. GC形成过程中的FAF1、Bcl-2和Survivin蛋白表达及与细胞凋亡的关系在CSG→CAG→IM→AH→GC发展过程中,FAF1的阳性表达率随病变程度加重而逐渐降低,分别为72.6%,65.5%,63.8%,54.3%,36.8%,AH组较CSG阳性率降低(p<0.05),GC组较CSG、CAG、IM组明显降低(p<0.01);Bcl-2的阳性表达率随病变程度加重而逐渐升高,分别为16.1%,21.8%,32.7%,50.0%,61.5%,其中IM组较CSG组阳性率升高(p<0.05);AH、GC组较CSG、CAG组阳性率明显升高(p<0.01);Survivin蛋白在CSG组织中未见表达,在非癌性病变组织中表达程度较弱,在胃癌组织中表达程度较高,分别为0,9.1%,17.3%,45.7%,63.1%,AH、GC组较CSG、CAG、IM组阳性率明显升高(p<0.01)。
细胞凋亡指数(AI)在CSG、CAG阶段逐渐升高,在AH、GC阶段逐渐降低,CAG、IM组较CSG组AI明显升高(p<0.01);AH、GC组较CSG、CAG、IM组AI明显降低(p<0.01)。
在CSG→CAG→IM→AH→GC发展过程中,FAF1阳性表达者凋亡指数均高于FAF1阴性,且各组均具有统计学意义(p<0.05,p<0.01);CAG、IM、AH、GC组Bcl-2阳性表达者凋亡指数均低于Bcl-2阴性,且在IM、AH及GC组具有统计学意义(p<0.05,p<0.01);CAG、IM、AH、GC组Survivin阳性表达者凋亡指数均低于Survivin阴性,且具有统计学意义(p<0.05)。
在CSG→CAG→IM→AH→GC发展过程中,FAF1的表达与病变恶性程度呈负相关(r=-0.251,p<0.05),Bcl-2、Survivin的表达与病变恶性程度呈正相关(r=0.361,0.535,p均<0.01)。FAF1阳性率与Bcl-2和Survivin阳性率呈负相关(r=-0.958、-0.971,p均<0.05),Bcl-2阳性率与Survivin阳性率呈正相关(r=0.995,p<0.01)。FAF1的阳性率与凋亡指数呈正相关趋势(r=0.738,p>0.05),Bcl-2和Survivin的阳性率与凋亡指数呈负相关趋势(r=-0.748、-0.782,p均>0.05)。
3. GC形成过程中H pylori感染与细胞凋亡的关系在CSG组,H pylori阳性AI高于H pylori阴性,差异有统计学意义(t' =2.055,p<0.05),而在GC组,H pylori阳性AI低于H pylori阴性,差异有统计学意义(t' =2.817,p<0.05),在其余三组之间差别无统计学意义(p>0.05)。
4. GC形成过程中H pylori感染对FAF1、Bcl-2和Survivin蛋白表达的影响H pylori阳性AH、GC组FAF1阳性表达率低于H pylori阴性组,且在GC组具有统计学意义(p<0.05),CSG、CAG和IM组H pylori阳性者FAF1阳性表达率略高于H pylori阴性组,但无统计学意义(p>0.05)。H pylori阳性CSG、CAG、IM、AH、GC组Bcl-2表达阳性率均高于H pylori阴性组,且在GC组具有统计学意义(p<0.05)。H pylori阳性CAG、IM、AH、GC组Survivin表达阳性率均高于H pylori阴性组,且在AH、GC组具有统计学意义(p<0.05)。
第二部分:
1. GC形成过程中FAF1、Bcl-2和Survivin mRNA的表达水平
FAF1mRNA在不同胃黏膜病变组织中均能检测到表达,在GC组mRNA相对表达量较低。Bcl-2mRNA在CSG→CAG→IM→AH→GC中阳性表达率分别为22.6%(14/62),30.9%(17/55),40.4%(21/52),58.7%(27/46),69.2%(45/65)。SurvivinmRNA阳性表达率分别为0,12.7%(7/55),25.0%(13/52),54.3%(25/46),75.4%(49/65)。FAF1mRNA在CSG→CAG→IM→AH→GC表达水平分别为0.136±0.008,0.131±0.009,0.128±0.010,0.094±0.032,0.006±0.003;Bcl-2mRNA表达水平分别为0.095±0.015,0.115±0.012,0.173±0.027,0.224±0.042,0.368±0.036;Survivin mRNA表达水平分别为0,0.068±0.007,0.347±0.060,0.553±0.080,1.646±0.356。可以看到,随着恶变程度的进展,FAF1mRNA的表达量逐渐下降,而Bcl-2和SurvivinmRNA表达阳性率和表达量逐渐上升。三个基因在IM阶段开始有表达差异,在GC组差异最为显著,AH组次之。
2. GC形成过程中FAF1、Bcl-2和Survivin mRNA表达的相关性分析经Spearman Correlations等级相关检验,在CSG→CAG→IM→AH→GC发展过程中,FAF1mRNA的表达与病变恶性程度呈负相关(r=-0.827,p<0.01),Bcl-2、Survivin mRNA表达与病变恶性程度呈正相关(r分别0.945,0.918,p均<0.01)。经Bivariate Correlations分析,CSG→CAG→IM→AH→GC发展过程中,FAF1mRNA表达量与Bcl-2和SurvivinmRNA表达量呈负相关(r分别为-0.911、-0.890,p均<0.01),Bcl-2 mRNA表达量与SurvivinmRNA表达量正相关(r=0.906,p<0.01)。
3. GC形成过程中FAF1、Bcl-2和Survivin三者基因表达和蛋白表达的相关性分析
经Bivariate Correlations分析,在CSG→CAG→IM→AH→GC发展过程中,FAF1基因与蛋白表达呈正相关(r=0.298,p<0.01),Bcl-2基因与蛋白表达呈正相关(r=0.324,p<0.01),Survivin基因与蛋白表达呈正相关(r=0.403,p<0.01),均具有一致性。
4. GC形成过程中FAF1、Bcl-2和Survivin mRNA的表达与H pylori感染状况之间的关系
在CSG和CAG组中,H pylori阳性者FAF1mRNA的表达略高于H pylori阴性,在IM组始这种趋势发生改变,在AH、GC组H pylori阳性FAF1mRNA的表达均明显低于H pylori阴性,差异有统计学意义(p<0.05,p<0.01);Bcl-2 mRNA的表达在IM、AH、GC组H pylori阳性均明显高于H pylori阴性,差异有统计学意义(p<0.05,p<0.01);Survivin mRNA的表达在AH、GC组H pylori阳性均明显高于H pylori阴性,差异有统计学意义(p<0.05)。随着胃黏膜恶变程度的加重,H pylori感染对FAF1mRNA的表达起下调作用,而对Bcl-2mRNA和SurvivinmRNA的表达起上调作用。
第三部分:
1. FAF1、Bcl-2和Survivin蛋白表达与胃癌各临床病理特征的相关性
相关性分析显示,FAF1表达与胃癌患者肿瘤大小、病理组织学分级、肿瘤的浸润程度、有无淋巴结转移、有无远处转移、TNM临床分期密切相关(p<0.01)。Bcl-2表达与肿瘤的浸润程度、有无淋巴结转移、TNM临床分期密切相关(p<0.01)。Survivin表达与组织学分级、肿瘤的浸润程度、TNM临床分期密切相关(p<0.05, p<0.01)。同时,相关性分析显示:胃癌中FAF1表达与Bcl-2和Survivin表达呈负相关(r_s=-0.236,r_s=-0.293,p均<0.01),Bcl-2和Survivin表达呈正相关(r_s=0.210,p<0.05)。
2. FAF1、Bcl-2和Survivin表达和临床病理学特征的预后分析
经单因素分析显示,FAF1、Bcl-2和Survivin的表达、肿瘤的大小、发生部位、肿瘤浸润深度、组织学分级、有无淋巴结转移、有无远处转移、TNM临床分期状况均是影响生存的预后因素,其中FAF1的表达为保护性因素,其它均为危险性因素。多因素分析显示FAF1、Bcl-2和Survivin的表达均不能成为影响患者总生存的独立预后因素。
3. FAF1、Bcl-2和Survivin表达对胃癌根治术患者术后生存的影响
随着FAF1表达程度的增加,中位生存时间延长,而随着Bcl-2和Survivin表达程度的增加,中位生存时间缩短。FAF1三组比较,1年、3年和5年生存率比较均有显著性差异(χ~2=1.029,χ~2=2.302,χ~2=6.218,p均<0.01);Bcl-2四组比较,1年生存率未见差异(χ~2=2.201,p=0.532),3年和5年生存率比较均有显著性差异(χ~2=13.102,χ~2=3.017,p均<0.01);Survivin四组比较,1年、3年和5年生存率比较均有显著性差异(χ2= 36.463,χ2=43.787,χ2= 8.646,p均<0.01)。Log-Rank法生存曲线配对比较,FAF1三组之间均有显著差异(p<0.01,p<0.05),Bcl-2组除“-”与“+”外,其余各组之间均有显著性意义(p<0.01, p<0.05)。Survivin组除“-”与“+”、“+”与“++”外,其余各组之间均有显著性意义(p<0.01,p<0.05)。
结论
1.从蛋白水平和细胞水平分析FAF1、Bcl-2和Survivin三个凋亡相关基因在胃黏膜癌变(CSG→CAG→IM→AH→GC)过程中的变化规律,显示了FAF1表达水平逐渐降低,Bcl-2和Survivin表达水平逐渐升高,相应的由FAF1介导和调控的胃黏膜细胞凋亡诱导作用逐渐减弱,而Bcl-2和Survivin介导的凋亡抑制作用逐渐增强,尤其发展到AH阶段后凋亡过程受到明显阻遏,凋亡指数(AI)明显降低,凋亡失衡而导致了胃癌的发生。
2.从基因水平和蛋白水平研究在胃黏膜癌变过程中的H pylori感染对FAF1、Bcl-2和Survivin的调控作用,显示了H pylori感染下调FAF1mRNA的表达, FAF1蛋白表达水平降低,而上调Bcl-2和SurvivinmRNA的表达, Bcl-2和Survivin蛋白表达水平增高,提示了H pylori感染引起FAF1、Bcl-2和Survivin基因调控失衡可能是胃癌变的机制之一。
3.临床分析显示,FAF1、Bcl-2和Survivin的表达与胃癌的生物学行为及临床病理特征密切相关,对胃癌患者预后有重要影响。FAF1高表达者,中位生存时间延长,生存率提高。Bcl-2和Survivin高表达者,中位生存时间缩短,生存率下降。
Investigated background and objective It was knowned that H pylori infection was a definited carcinogenic agent and the first impulse factor of homo-sapiens gastric carcinogenesis,especially typical intestine type in the process of chronic superficial gastris (CSG)- chronic atrophic gastris(CAG)- intestinal melaplasia(IM)- atypical hyperplasia(AH)- gastric carcinoma(GC) , which had been prefered by Correa.GC was a species of genopathy and its carcinogenesis was the gradually accumulated change of multiple genes those possibly made roles in diaparate phases. It was associated with not only proto- oncogene activation and anti-oncogene mutation ,but also cell apoptosis genes, which intimately participate in the gastric carcinogenesis.Possibly apoptosis related genes make critical roles in the process of gastric cancerization with H pylori infection. At present , it is not yet clarity that the sure effect and the mechanism of cell apoptosis regulation with H pylori infection,also the correlation with them ,and the apoptosis inducing and inhibiting genes maybe make different roles in different phases.So it is necessary to explore the pro- apoptotic and antiapoptotic machanism of them in the process of gastric cancerization with H pylori infection. Fas-associated factor 1 (FAF1)was a protein recently discoved and had been demonstrated to be a component of the death inducing signaling complex (DISC) in Fas-mediated apoptosis, whose N-termial region specificly combinated with Fas to enhance the Fas-mediated apoptosis. FAF1 was down-regulated in gastric cancer tissue specificly. Now it is known little about the role of FAF1,and our early study had tentatively confirmed the prior conclusion,furthermore,no report about the correlation and mechanism of action between H pylori infection and FAF1 as a proapoptotic factor in gastric cancerization. B-cell lymphoma/Leukemia-2(Bcl-2) was a anti- apoptotic gene which was discovered earliestly and investigated deeply and extensively up to now.It was known that Bcl-2 was a most important factor to inhibit the apoptosis of tumor cell. Survivin was a member of inhibitors of apoptosis proteins(IAP) family and a most strongest antiapoptotic factor,which affected on the assemble point of all apoptosis pathway.Survivin expression was negative or low in the normal ripe human tissue,but positive and high in human majority tumor tissue, which to hint it important in carcinogenesis and deve- lopment .The machanism of action yet know little between H pylori infection and Bcl-2 as antiapoptotic factors in gastric cancerization,also together with FAF1 as a proapoptotic factor. In conclusion,in this study we aim to clarity the correlation and possible machanism of action between H pylori infection and those genes related with cell apoptosis regulation, furthermore, combining with clinical correlated information, to explore the effect of those genes on the early diagosis , infiltration ,metastasis and prognosis of gastric cancer .Which to offer some referred molecular biological parameters for the early diagosis and treatment of gastric cancer.
Methods To explore the correlation between H pylori infection and FAF1 ,Bcl-2 and Survivin expression in gastric carcinogenesis,also cell apoptosis,H pyloriinfection was evaluated by Rapid Urease Test ,Methylene blue and Warthin-Starry staining method,and the expression of FAF1 ,Bcl-2 and Survivin were detected by immunohistochemical (IHC) staining ,while the level of cell apoptosis were detected by terminal deoxynucleosides mediated nick end labeling (TUNEL)staining,including 62 cases of chronic superficial gastris (CSG), 55 cases chronic atrophic gastris(CAG),52 cases intestinal melaplasia (IM) ,46 cases atypical hyperplasia(AH),65 cases gastric carcinoma(GC). Furthermore,to explore the correlation between H pylori infection and genes transcription,the expressin level of FAF1 mRNA,Bcl-2 mRNA and Survivin mRNA were detected by Fluorescent Qanlity Real-time polymerase chain reaction.Additionaly,combinating with the pathematology and follow-up data of clinical cases , to explore the effect of those genes on the early diagosis , infiltration ,metastasis and prognosis of gastric cancer.
Results
Chapter I
1. The positive rate of H pylori infection during the course of gastric cancer progression. The positive rate of H pylori infection was 53.6% with three methods combined,and increased with the degree of carcinogenesis of gastric mucosa .The positive rate was 30.6%,49.1%,55.8%,65.2%,69.2%,respectively. The infection rate of H pylori in CAG,IM,AH,GC were higher than that in CSC respectively(p<0.05),and GC were higher than CAG(p<0.05).
2. The correlation between the expression of FAF1,Bcl-2 and Survivin protein and cell apoptosis. The positive rate of FAF1 protein expression decreased with the degree of carcinogenesis of gastric mucosa. The positive rate was 72.6%,65.5%,63.8%,54.3%,36.8% respectively. The positive rate of FAF1 protein expression in AH were lower than that in CSG (p<0.01),and GC were lower than CSG,CAG,IM respectively(p<0.01).While, the positive rate of Bcl-2 and Survivin protein expression increased with the degree of carcino- genesis of gastric mucosa. The positive rate of Bcl-2 expression was 16.1%, 21.8%,32.7%,50.0%,61.5% respectively. The positive rate of Bcl-2 expression in IM was higher than in CSG (p<0.05),and AH and GC were higher than CSG and CAG,respectively(p<0.01).The expression of Survivin was negative in CSG,and weak in non-carcinoma pathological tissue,but strong in gastric cancer tissue. The positive rate of Survivin expression was 0,9.1%,17.3%,45.7%,63.1% respectively. The positive rate of Survivin expression in AH and GC were significant higher than in CSG ,CAG and IM(p<0.01).
The AI increased in the phase of CSG and CAG, while decreased in the phase of AH and GC gradually. The AI in CAG and IM were significant higher than in CSG (p<0.01), while AH and GC were lower than CSG,CAG and IM respectively(p<0.01).
During the course of gastric cancer progression ,the AI with FAF1 positive expression were higher than that with FAF1 negative among all groups(p<0.05, p < 0.01),howerver, the AI of Bcl-2 positive expression were lower than negative ,especially in IM,AH and GC(p<0.05,p<0.01),and the AI of Survivin positive expression were lower than negative in CAG, IM,AH and GC( p<0.05).
During the course of gastric cancer progression, there was negative correlation between FAF1 positive and the degree of carcinogenesis of gastric mucosa(r=-0.251,p<0.05), but there were positive correlation between Bcl-2 and Survivin positive and the degree of carcinogenesis of gastric mucosa (r=0.361, 0.535 respectively, p all<0.01).There were negative correlation between FAF1 positive rate and Bcl-2 and Survivin positive rate(r=-0.958, -0.971 respectively,p all < 0.05),howerver positive colleration was found between Bcl-2 and Survivin postive rate(r=0.995,p<0.01). There was only positive correlation tendency between FAF1 positive rate and AI(r=0.738,p>0.05),while negative correlation tendency between Bcl-2 and Survivin positive rate and AI(r=-0.748,-0.782, p all >0.05).
3. The correlation between H pylori infection and cell apoptosis. We found the AI of H pylori positive was higher than that of H pylori negative in CSG (t' =2.055,p<0.05),while lower in GC (t' =2.817,p<0.05).There were no difference in other groups(p>0.05).
4 . The correlation between H pylori infection and the expression of FAF1,Bcl-2 and Survivin protein. We found the positive rate of FAF1 protein expression with H pylori positive was lower than that of H pylori negative in AH and GC, and there was significant difference in GC(p<0.05). There were no difference in other groups, though the positive rate of FAF1 protein expression with H pylori positive was a little high than that with H pylori negative(p>0.05).The positive rate of Bcl-2 protein expression with H pylori positive was higher than that of H pylori negative in all group,but only there was significant difference in GC(p<0.05). The positive rate of Survivin protein expression with H pylori positive was higher than that of H pylori negative in all group,but only there was significant difference in AH and GC(p<0.05).
Chapter II
1. The expression of FAF1,Bcl-2 and Survivin mRNA during the course of gastric cancer progression. During the course of gastric cancer progression (CSG→CAG→IM→AH→GC),FAF1mRNA expression was detected in different gastric mucosa lesion groups,and the relative quantity in GC was lower. The Bcl-2 mRNA positive rate was 22.6%(14/62),30.9(17/55),40.4%(21/52), 58.7%(27/46),69.2%(45/65) respectively. The Survivin mRNA positive rate was 0,12.7%(7/55),25.0%(13/52),54.3%(25/46),75.4%(49/65)respectively.
The level of FAF1mRNA expression in different groups were0.136±0.008, 0.131±0.009,0.128±0.010,0.094±0.032,0.006±0.003 respectively. Bcl-2 mRNA were 0.095±0.015,0.115±0.012,0.173±0.027,0.224±0.042,0.368±0.036 respectively. SurvivinmRNA were 0, 0.068±0.007, 0.347±0.060, 0.553±0.080, 1.646±0.356.We can conclude FAF1 mRNA decreased gradually with the degree of carcinogenesis of gastric mucosa ,but Bcl-2 mRNA and Survivin increased in the same course. The level of FAF1 mRNA expression were lower in IM,AH and GC than that in CSG(p<0.05,p<0.01),and AH was lower than IM(p<0.01),including GC was lower than IM and AH(p<0.01). The level of Bcl-2 mRNA expression were higher in IM,AH and GC than that in CSG and CAG(p<0.01),and AH was higher than IM(p<0.01),including GC washigher than IM and AH(p<0.01). The level of Survivin mRNA expression were higher in IM,AH and GC than that in CAG(p<0.05, p<0.01),and AH was higher than IM(p<0.05),including GC was higher than IM and AH(p<0.01).The level of three genes expression showed difference in IM firstly, the most significant in GC, Following in AH.
2. The correlation among the level of FAF1mRNA ,Bcl-2 mRNA and Survivin mRNA during the course of gastric cancer progression. During the course of gastric cancer progression, there was negative correlation between the level of FAF1 mRNA expression and the degree of carcinogenesis of gastric mucosa (r=-0.827,p<0.01), but there were positive correlation between the level of Bcl-2 and Survivin mRNA expression and the degree of carcinogenesis of gastric mucosa(r=0.945, 0.918 respectively, p all < 0.01) with Spearman Correlations test .
There were negative correlation between the level of FAF1 mRNA expression and the level of Bcl-2 and Survivin mRNA expression (r=-0.911, -0.890 respectively,p all<0.01),howerver positive colleration was found between Bcl-2 mRNA and Survivin mRNA (r=0.906,p<0.01) with Bivariate Correlations analysis.
3. The correlation between mRNA and protein of FAF1,Bcl-2 and Survivin during the course of gastric cancer progression. During the course of gastric cancer progression ,there were positive correlation between the level of FAF1,Bcl-2 and Survivin mRNA expression and the level of Bcl-2 and Survivin protein expression (r=-0.298, 0.324, 0.403 respectively,p all<0.01),so there were consistency between them respectively.
4. The correlation between H pylori infection and the expression of FAF1,Bcl-2 and Survivin mRNA during the course of gastric cancer progression We found the level of FAF1 mRNA expression with H pylori positive was little higher than that of H pylori negative in CSG and CAG , but this tendency altered in IM, howerever, the level of FAF1 mRNA expression with H pylori positive was lower than that of H pylori negative in AH and GC(p<0.05,p<0.01).The level of Bcl-2 mRNA expression with H pylori positive was higher than that of H pylori negative in IM,AH and GC respectively(p<0.05, p<0.01). The level of Survivin mRNA expression with H pylori positive was higher than that of H pylori negative in IAH and GC respectively(p<0.05). H pylori infection can gradually down-regulated the level of FAF1mRNA expression,but up-regulated the expression of Bcl-2 and SurvivinmRNA expression during the course of gastric cancer progression.
Chapter III
1. The correlation on FAF1,Bcl-2 and Survivin protein expression and clinical pathological characteristics in gastric cancer It was showed that there were close correlations between FAF1 expression and tumor size, Histological grade, Tumor infiltration, nodus lymphaticus metastasis, distance metastasis and TNM clinical stage( p<0.01),and between Bcl-2 expression and tumor infiltration, nodus lymphaticus metastasis, and TNM clinicalStage( p<0.01), meanwhile between Survivin expression and tumor histological grade, Tumor infiltration, and TNM clinical stage(p <0.05, p <0.01).There were negative correlation between the level of FAF1 protein expression and the level of Bcl-2 and Survivin protein expression in gastric cancer (r=-0.236,-0.293, respectively,p all<0.01),howerver positive colleration was found between Bcl-2 protein and Survivin protein (r=0.210,p<0.05) .
2. The prognosis factors investigation on the correlation of FAF1,Bcl-2 and Survivin and clinical pathological characteristics in gastric cancer. Single factor COX risk model assay showed the level of FAF1,Bcl-2 and Survivin expression ,tumor size , anatomic site, tumor infiltration, nodus lymphaticus metastasis, distance metastasis and TNM clinical stage histological grade all were markely correlated with the prognosis of patients with gastric cancer by radical resection.FAF1 expression was protect factor ,and others were risk factors. Independent risk factors analysis showed FAF1,Bcl-2 and Survivin were not indepent risk factors which influenced on the prognosis of patients with gastric cancer radical resection.
3. The correlation on FAF1,Bcl-2 and Survivin expression and survival in gastric cancer by radical resection.The median surviral time was prolonged and surviral rate increased with the degree of FAF1 expression increased, Howerver,with Bcl-2 and Survivin expression increased the median surviral time was shorten and surviral rate decreased. There were signifcant defferences for 1 year, 3 years and 5years surviral rate (χ~2=1.029,χ~2=2.302,χ~2=6.218,respectively, p all <0.01). There were significant differences for 3 years and 5years surviral rate(χ~2=13.102,χ~2=3.017,respectively,pall<0.01) among the Bcl-2 groups.There was significant difference among the Survivin groups (-,+,++,+++)for 1year, 3 years and 5years surviral rate (χ~2=36.463,χ~2=43.787,χ~2=8.646,respectively, pall<0.01).With Log-Rank methods,there were significant difference among the different degree three groups of FAF1.Besides Bcl-2(- and+) groups,there were significant difference in other Bcl-2 groups(p<0.01, p<0.05). Besides survivin(- and +,+and ++) groups, there were significant difference in other survivin groups(p<0.01, p<0.05).
Conclusion
1. In this study on the protein and cell fields ,we noticed the FAF1,Bcl-2 and Survivin related apoptosis regulation genes expression level altered obviously in the process of CSG→CAG→IM→AH→GC,with FAF1 expression increased and Bcl-2 and Survivin decreased, which showed proapoptosis factor FAF1 mediated and regulated cell apopotosis attenuated, while anti- proapoptosis factors Bcl-2 and Survivin mediated cell apoptosis to enhance , especially in AH the apoptosis process was repressed obviously ,with AI decreasing the same time, so the disbalance between cell proliferation and apopotosis to induce gastric carcinogenesis.
2.In this study on the gene and protein fields ,we explored the relationship between H pylori infection and FAF1,Bcl-2 and Survivin,and found H pylori infection could down-regulated the level of FAF1 gene and portein expression, but up-regulated the expression of Bcl-2 and Survivin genes and proteins expression in the process of CSG→CAG→IM→AH→GC ,which all showed the disblance between the FAF1 and Bcl-2,Survivin possibly was a mechanism of gastric carcinogenesis induced by H pylori infection.
3. In our clinical study, we found FAF1,Bcl-2 and Survivin all were intimately correlated with the biological behaviour of gastric cancer and clinical pathology characteristic, also were factors which influenced on the surviral prognosis of patients with gastric cancer radical resection. he higer FAF1 protein level was correlated with good prognosis,and higer Bcl-2 and Survivin protein level were correlated with poor prognosis.
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