EBV、mdm2和p53基因异常在胃癌发生发展中的作用

Epstein-Barr virus and aberrant expression of mdm2 and p53 in pathogenesis and development of gastric carcinoma

目的:探讨EBV相关胃癌(EBV associated gastric carcinoma, EBVaGC)组织mdm2和p53基因异常与EBV感染的关系. 方法:应用免疫组化技术检测13例EBVaGCs、45例临床病理资料与之匹配的EBV阴性胃癌(EBV negative gastric carcinomas,EBVnGCs)以及58例相应癌旁组织中p53和mdm2蛋白的表达;PCR-SSCP银染技术结合DNA测序检测p53基因exon 5-8突变. 结果:(1)胃癌组p53和mdm2蛋白阳性率分别为86.2% (50/58)和29.3%(17/58),癌旁组织组p53和mdm2蛋白均为阴性,胃癌组p53和mdm2蛋白阳性率均明显高于癌旁组织组,两两间有极显著性差异(X2=50.000, P=0.0 000<0.01;X2=15.059,P=0.0 001<0.01).(2) EBVnGC组p53和mdm2蛋白阳性率与EBVaGC组p53 和mdm2蛋白阳性率均无明显差异,但EBVaGC组p53 蛋白过表达率(15.4%)明显低于EBVnGC组(57.8%),两组间有极显著性差异(X2=7.2 593,P=0.0 085<0.01). (3)mdm2蛋白阳性表达与p53蛋白过表达呈显著正相关(X2=11.1 839,P=0.0 008<0.01,r=0.4 391).(4)2例EBVnGCs检测到p53基因突变,突变均位于exon 5,13 例EBVaGCs和58例相应癌旁组织均未检测到p53基因突变;EBVaGC组p53基因突变率与EBVnGC组相比无显著性差异(P=0.5989). 结论:p53基因突变可能并非胃癌组织中p53蛋白异常累积的主要原因;mdm2蛋白可通过抑制野生型p53蛋白的功能而产生致癌作用;胃癌组织中EBV感染与p53蛋白的异常表达有关,而与mdm2蛋白的异常表达以及p53基因突变无显著相关性.

AIM: To investigate the role of p53 and mdm2 gene abnormality in oncogenesis and development of Epstein-Barr virus (EBV) -associated gastric carcinoma (EBVaGC) and to explore the relationship between EBV infection and P53 and mdm2 protein expression. METHODS: p53 gene mutation in exon 5-8 was detected by polymerase chain reaction and single strand conformation polymorphism analysis (PCR-SSCP), and DNA sequencing. p53 and mdm2 protein expression was tested by immunohistochemistry in EBVaGCs (n=13), EBVnGCs (EBV negative gastric carcinomas, n = 45) with matched clinicopathological parameters and corresponding adjacent tissues of gastric carcinoma (n=58). RESULTS: The positive rates of p53 and mdm2 protein in gastric carcinomas were significantly higher than those in corresponding adjacent normal tissues (86.2%, 29.3% vs 0%, 0% respectively; P<0.01). There were no significant difference between the positive rates of p53 and mdm2 protein in EBVnGCs and EBVaGCs. The overexpression rate of p53 protein was 15.4% (2/13) in EBVaGCs. This was in marked contrast to the rate of 57.8% (26/45) in EBVnGCs (X2=7.2593, P=0.0 085<0.01). There was significant positive correlation between mdm2 expression and p53 overexpression (X2 =11.1839, P= 0.0 008<0.01, r= 0.4 391). p53 gene mutation was found in only 2 cases of EBVnGCs and both occurred at exon 5. No p53 gene mutation was detected in 13 cases of EBVaGCs and 58 corresponding adjacent tissues. CONCLUSION: Abnormal accumulation of p53 protein might not result from p53 gene mutation. mdm2 protein may play an important role in the pathogenesis of gastric carcinoma through suppressing the function of wild type p53 protein. The infection of EBV relates to the abnomal expression of p53 protein, but not to the abnomal expression of mdm2 protein and p53 gene mutation in gastric carcinoma