一组与胃黏膜病变演化及早期癌变相关基因的鉴定及生物学意义  

Identification of biomarkers for early detection in gastric cancer and its clinical biological significance

作　　者：郭瑞芳[1] 臧师竹[1] 房静远[2] 张亮[3] 胡伏莲[4] 李文梅[1] 张经余[1] 吕有勇[1] 

机构地区：[1]北京大学临床肿瘤学院,北京市肿瘤防治研究所,北京100142 [2]上海交通大学附属仁济医院消化内科 [3]北京大学生物芯片北京国家工程中心 [4]北京大学第一临床医院消化内科

出　　处：《北京大学学报（医学版）》2009年第3期353-360,共8页Journal of Peking University:Health Sciences

基　　金：国家重点基础研究发展规划项目基金(2004CB518708);内蒙古自治区自然科学基金项目(20080404Zd26)~~

摘　　要：目的:鉴定能够特异性识别肿瘤生物学行为和预测肿瘤早期发生的分子标志谱,为胃癌早期诊断和有效防治提供实验依据和理论基础。方法:利用优化的70 mer的22K-Oligo基因芯片杂交和生物信息学分析,建立了胃癌(gastric cancer,GC)和癌旁形态学正常组织(normal appearing tissue,NAT)差异基因表达谱。通过设立以混合的正常胃黏膜组织作为共同参照(common reference,CR),将胃癌和配对癌旁形态学正常组织表达无明显差别的一类基因分离出来,这些基因主要是参与细胞增殖、代谢和分化过程的调控。在此基础上鉴定出一组与胃黏膜病变演化和细胞癌变早期相关的差异表达基因。结果:利用半定量RT-PCR,免疫组织化学染色方法对差异表达基因进行了验证,获得了与芯片表达谱数据一致的结果。进一步的生物信息学分析和实验研究明确了3个有代表性的基因(EGR1、CYR61和ADAMTS1)在胃癌及癌旁形态学正常组织、异型增生、肠上皮化生和非癌患者正常胃黏膜组织中的表达变化。癌和配对形态学正常组织表达水平未见明显差异的这一组基因,在肠化和异型增生组织中,mRNA表达水平明显高于正常胃黏膜组织。结论:肿瘤患者癌旁形态学正常组织中的基因表达模式已经发生了改变。EGR1、CYR61和ADAMTS1基因过量表达参与胃黏膜病变的演化过程,这一组基因的异常表达可能是胃癌发生的早期事件之一。Objective：To systematically understand the cellular and molecular mechanism of gastric cancer （GC） development and to discover early diagnosis and predictive biomarkers, which will be used for early diagnosis and novel treatment targets. Methods： 70 mer 22 K-oligonucleotide microarrays and bioinforrnatic analysis were conducted to recognize gene expression profiles in GC and normal appearing tissue （NAT）. The control group was collected from non-tumor patients including 20 specimen mixture as a common reference （CR） and 5 individuals as additional control. Our results showed that 837 different expression genes （DEGs） were identified in GC while 570 DEGs were in NATs by Bayesian analysis （P 〈0. 001 ,Fold change 〉2.0） as compared respectively with CR. An interesting finding is that we i- dentified 67 over-expressed genes in both GC and NAT tissues, and these gene expression alterations could not he detected by comparison of GC with NATs, which were normally used in routine experiment design. Most of these genes were involved in the control of cell proliferation, metabolism and differentia- tion. Results：These differential expressed genes were confirmed at mRNA and protein levels in primary tumors using RT-PCR and immunohistochemistry （IHC）. The results showed that three genes, EGR1, CYR61 and ADAMTS1 were over expressed in both GC and NATs at mRNA level. These results were consistent with oligo microarray data. Another interesting finding is that these three genes were also over-ex- pressed in intestinal metaplasia （IM） and dysplasia （DYS）, which indicated that these three genes might be potential biomakers for early detection of GC. Condusion： Through the systematic analysis of gene expression profiles in GC tissues, NAT and CR normal tissues, we identified a group of genes over-ex- pressed both in GC and precancerous lesions, which might be potential biomarkers for early GC diagno- sis.

关 键 词：胃肿瘤 基因表达谱 早期诊断 胃黏膜 

分 类 号：R735.2[医药卫生—肿瘤]