Gorgoulis V G, Zoumpourlis V, Rassidakis G Z, Karameris A, Rassidakis A N, Spandidos D A, Kittas C
Department of Histology and Embryology, University of Athens, School of Medicine, Greece.
J Pathol. 1996 Oct;180(2):129-37. doi: 10.1002/(SICI)1096-9896(199610)180:2<129::AID-PATH646>3.0.CO;2-8.
Forty-one bronchogenic carcinomas were investigated for expression of MDM2 protein isoforms and their relationship to p53 protein levels and p53 gene alterations using molecular and immunohistochemical techniques. The findings were correlated with the pathological features of the carcinomas. MDM2 protein was overexpressed in 26 cases (63 percent). Western blot analysis with two monoclonal antibodies, 1B10 and IF2, revealed three MDM2 protein isoforms, p90, p57 and p76/74. p90 and p57 are capable of interacting with p53 protein, while p76/74 is not. Various patterns of MDM2 isoforms were seen. Although no correlation between the patterns and pathological features was observed, lymph node metastases were more frequent in the cases with MDM2 overexpression (P < 0.005). In 3 out of 17 specimens of normal lung tissue examined, there was a low level of expression of p90. Molecular analysis revealed that MDM2 overexpression was a consequence of increased transcription rather than MDM2 gene amplification. p53 protein was overexpressed in 21 cases (51 percent) and p53 gene alterations (mutations + allelic deletions) were detected in 23 patients (56 percent). A high degree of concordance (76 percent) between p53 mutations and p53 staining was noticed (P < 10(-5)). p53 gene alterations were significantly associated with lymph node disease (P < 0.01). MDM2 and p53 proteins were simultaneously detected in 21 cases (51 percent), of which 17 (42 percent) showed p53 and MDM2 overexpression. The latter group was positively correlated with p53 mutations (P < 0.05). A strong correlation between MDM2/p53 co-expression and lymph node metastases was observed (P < 0.001). The findings suggest that MDM2 overexpression is a common event in bronchogenic carcinoma. The selective expression of some MDM2 isoforms in neoplastic tissue and not in the surrounding normal areas underscores the pathological role of the various MDM2 products. Finally, the coexistence of MDM2 protein(s) and p53 aberrations (mutations and/or overexpression) in a subset of lung carcinomas may be indicative of a 'gain of function' phenotype, with more aggressive characteristics.
采用分子和免疫组化技术对41例支气管源性癌进行MDM2蛋白异构体表达及其与p53蛋白水平和p53基因改变关系的研究。研究结果与癌的病理特征相关。26例（63%）MDM2蛋白过表达。用两种单克隆抗体1B10和IF2进行蛋白质印迹分析，显示出三种MDM2蛋白异构体，即p90、p57和p76/74。p90和p57能够与p53蛋白相互作用，而p76/74则不能。观察到MDM2异构体的多种模式。虽然未观察到这些模式与病理特征之间的相关性，但MDM2过表达的病例中淋巴结转移更为常见（P<0.005）。在所检查的17例正常肺组织标本中，有3例p90表达水平较低。分子分析显示，MDM2过表达是转录增加而非MDM2基因扩增的结果。21例（51%）p53蛋白过表达，23例患者（56%）检测到p53基因改变（突变+等位基因缺失）。注意到p53突变与p53染色之间高度一致（76%）（P<10⁻⁵）。p53基因改变与淋巴结病变显著相关（P<0.01）。21例（51%）同时检测到MDM2和p53蛋白，其中17例（42%）显示p53和MDM2过表达。后一组与p53突变呈正相关（P<0.05）。观察到MDM2/p53共表达与淋巴结转移之间存在强相关性（P<0.001）。研究结果表明，MDM2过表达在支气管源性癌中是常见事件。某些MDM2异构体在肿瘤组织而非周围正常区域的选择性表达突出了各种MDM2产物的病理作用。最后，一部分肺癌中MDM2蛋白与p53异常（突变和/或过表达）共存可能提示具有更侵袭性特征的“功能获得”表型。
