Leite K R, Franco M F, Srougi M, Nesrallah L J, Nesrallah A, Bevilacqua R G, Darini E, Carvalho C M, Meirelles M I, Santana I, Camara-Lopes L H
Laboratory of Surgical and Molecular Pathology, Hospital Sirio Libanes, Sao Paulo, Brazil.
Mod Pathol. 2001 May;14(5):428-36. doi: 10.1038/modpathol.3880330.
Mutation of p53 is rare in localized prostate carcinoma. The oncoprotein MDM2, whose gene has a response element for p53, promotes the degradation of p53 protein and inhibits its transcriptional activation of genes related to cell cycle arrest and apoptosis, constituting a negative feedback control. We studied p53 and MDM2 expression by immunohistochemistry and looked for mutations in p53 exons 5 to 8 by polymerase chain reaction-single strand conformational polymorphism in 118 patients submitted to radical prostatectomy for localized prostate cancer. In 28 cases, we studied cell proliferation by immunohistochemistry, using antibody for Ki-67, and apoptosis by the deoxynucleotidyl transferase mediated dUTP biotin nick end labeling technique. Although no p53 mutations were found, p53 protein was detected in 31.4% of the cases, and these cases had higher Gleason scores (P = .03) and more advanced tumor stages (P = .02). MDM2 was overexpressed in 40.7% of the cases, and these cases had greater tumor volumes (P = .001). Tumors that were positive for both p53 and MDM2 were larger (P = .003) and of more advanced stage (P = .03). Within the 28-case subset, the proliferative index was higher among MDM2-positive tumors (P = .046), and the apoptotic index was lower among p53-positive tumors (P = .01). We conclude that, although p53 mutation is a rare event in prostate carcinogenesis, the detection of p53 protein by immunohistochemistry is common and is associated with decreased apoptosis and increased histologic grade and tumor stage. We also conclude that the overexpression of MDM2 has a role in prostate carcinogenesis, being frequently detected and associated with increased cell proliferation and tumor volume. Finally, we propose that the MDM2-positive/p53-positive phenotype identifies prostate cancers with aggressive behavior.
p53突变在局限性前列腺癌中较为罕见。癌蛋白MDM2的基因具有p53反应元件，可促进p53蛋白降解并抑制其对细胞周期阻滞和凋亡相关基因的转录激活，构成负反馈调控。我们通过免疫组织化学研究了p53和MDM2的表达，并采用聚合酶链反应-单链构象多态性方法在118例因局限性前列腺癌接受根治性前列腺切除术的患者中寻找p53外显子5至8的突变。在28例患者中，我们通过免疫组织化学使用Ki-67抗体研究细胞增殖，并采用脱氧核苷酸末端转移酶介导的dUTP生物素缺口末端标记技术研究凋亡。尽管未发现p53突变，但在31.4%的病例中检测到p53蛋白，这些病例的Gleason评分更高（P = 0.03）且肿瘤分期更晚（P = 0.02）。40.7%的病例中MDM2过表达，这些病例的肿瘤体积更大（P = 0.001）。p53和MDM2均呈阳性的肿瘤更大（P = 0.003）且分期更晚（P = 0.03）。在28例患者的亚组中，MDM2阳性肿瘤的增殖指数更高（P = 0.046），而p53阳性肿瘤的凋亡指数更低（P = 0.01）。我们得出结论，尽管p53突变在前列腺癌发生中是罕见事件，但通过免疫组织化学检测到p53蛋白很常见，且与凋亡减少、组织学分级增加和肿瘤分期相关。我们还得出结论，MDM2过表达在前列腺癌发生中起作用，经常被检测到并与细胞增殖增加和肿瘤体积增大相关。最后，我们提出MDM2阳性/p53阳性表型可识别具有侵袭性行为的前列腺癌。
