Blok P, Craanen M E, Dekker W, Offerhaus G J, Tytgat G N
Department of Pathology, Westeinde Ziekenhuis, The Hague, The Netherlands.
J Pathol. 1998 Sep;186(1):36-40. doi: 10.1002/(SICI)1096-9896(199809)186:1<36::AID-PATH150>3.0.CO;2-R.
Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5-8 of the p53 gene leading to mutated, usually immunohistochemically detectable p53 proteins. However, functional inactivation of wild-type p53, mimicking mutational inactivation, may also result from binding to overexpressed MDM2 protein. While these two mechanisms of p53 inactivation are considered to be mutually exclusive, no data exist as to whether MDM2 overexpression occurs during gastric carcinogenesis. MDM2 protein overexpression was therefore studied in relation to p53 protein accumulation in gastric carcinogenesis. Forty-five paraffin-embedded gastrectomy specimens from early gastric carcinomas were examined for the presence of chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia. The Lauren type was reassessed for all early carcinomas. p53 protein accumulation was examined using the monoclonal antibody DO-7. MDM2 protein overexpression was assessed with the monoclonal antibody SMP-14. Complete absence of nuclear p53 protein accumulation was observed in chronic active gastritis, chronic atrophic gastritis, and intestinal metaplasia, irrespective of the subtype. In gastric dysplasia (one mild, two moderate, one severe), only severe dysplasia was p53-positive. Intestinal-type (n = 20) and diffuse-type early gastric carcinoma (n = 25) were p53-positive in 70 and 52 per cent of the cases, respectively. MDM2 protein overexpression was not observed during gastric carcinogenesis, either in the p53-positive or in the p53-negative cases. In conclusion, it appears that functional inactivation of wild-type p53 by MDM2 protein overexpression plays no role in (early) gastric carcinogenesis.
在胃癌发生过程中，野生型p53的失活通常是由p53基因外显子5 - 8内的突变引起的，这些突变导致了通常可通过免疫组织化学检测到的p53蛋白发生突变。然而，野生型p53的功能失活，类似于突变失活，也可能是由于与过度表达的MDM2蛋白结合所致。虽然这两种p53失活机制被认为是相互排斥的，但关于MDM2在胃癌发生过程中是否过度表达尚无相关数据。因此，研究了MDM2蛋白过度表达与胃癌发生过程中p53蛋白积累的关系。对45例早期胃癌石蜡包埋的胃切除标本进行检查，以确定是否存在慢性活动性胃炎、慢性萎缩性胃炎、肠化生亚型和发育异常。对所有早期癌重新评估Lauren分型。使用单克隆抗体DO - 7检测p53蛋白积累。用单克隆抗体SMP - 14评估MDM2蛋白过度表达。在慢性活动性胃炎、慢性萎缩性胃炎和肠化生中，无论亚型如何，均未观察到核p53蛋白积累完全缺失。在胃发育异常（1例轻度、2例中度、1例重度）中，只有重度发育异常p53呈阳性。肠型（n = 20）和弥漫型早期胃癌（n = 25）中，p53阳性病例分别占70%和52%。在胃癌发生过程中，无论是p53阳性还是p53阴性病例，均未观察到MDM2蛋白过度表达。总之，MDM2蛋白过度表达导致野生型p53功能失活在（早期）胃癌发生中似乎不起作用。
