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The aberrant expression by the target genes of tumor supressor protein p53 in non- small cell lung cancer. A search for a new mechanism of carcinogenesis.

抑癌蛋白p53靶基因在非小细胞肺癌中的异常表达。

基本信息

批准号：
08670647
负责人：
EBINA Masahito
金额：
$ 1.22万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670647/
关键词：
lung cancer tumor supressor gene p53 p21Waf1 Cip1 MDM2 GADD45 Wafl Cipl Waf1 CiPl

项目摘要

While p53 overexpression is often associated with p53 mutaions, the abnormalities in downstream of p53 transactivation may also contribute to the overexpression and dysfunction of p53 protein. In this study, the expressions of p53, Mdm2, and p21WAF1/CIP1 were examined by immunohistochemistry, and the mutations of p21 and GADD45 were searched by PCR-SSCP in a cohort of 123 patients with NSCLC of all stages, incluging 71 primary lung tumors and 52 metastatic tumors. Sixty-three patients received potentially curative treatment (stages I,II and IIIA) and 60 patients palliative treatment (stages IIIB and IV). Of all tumors, 39% were positive for p53 (DO-7, Dako) and 18% were positive for Mdm2 (Ab-1, Oncogene Science). As for p21 (Ab-1, Oncogene Science), 75% of the tumors were negative while the rest of the tumors expressed variable amounts. While the expression of p53 and p21 was independent, Mdm2 appeared to be coexpressed with p53 (p2=0.013) and p21 (p2=0.001). In the patients treated with curarive intent, the probability of survival or development of metastases according to Kaplan-Meier method showed limited number of associations with p53 or Mdm2 expression. Cox proportional hazards model only associated the overexpression of p53 (p=0.0001) with shortened survival and the development of metastases in these patients. the results that no mutations were found in the coding region of p21 and GADD45, revealed the alterations of the p53 gene products are the main cause of the carcinogenesis. The heterogeneous expression of p53, Mdm2, and p21 in NSCLC suggested multiple mechanisms of transactivating or suppressing transactivation factors contributing to carcinogenesis.

虽然P53的过度表达通常与P53突变有关，但P53反式激活下游的异常也可能导致P53蛋白的过度表达和功能障碍。本研究采用免疫组织化学方法检测P53、MDM2和p21WAF1/CIP1的表达，用聚合酶链式反应-单链构象多态方法(PCR-SSCP)检测123例各期非小细胞肺癌(包括71例原发肺癌和52例转移癌)中p21和GADD45的突变情况。63名患者接受了潜在的根治治疗(I期、II期和IIIA期)，60名患者接受了姑息治疗(IIIB期和IV期)。在所有肿瘤中，39%的肿瘤P53(DO-7，DAKO)和18%的MDM2(抗体-1，癌基因科学)阳性。至于p21(Ab-1，癌基因科学)，75%的肿瘤为阴性，其余的肿瘤表达多种多样。Mdm2与p53(p2=0.013)、p21(p2=0.001)共同表达，而p53和p21的表达相互独立。根据Kaplan-Meier方法，在有治疗意向的患者中，生存或发生转移的概率与P53或MDM2表达的相关性有限。COX比例风险模型仅将P53的过度表达(p=0.0001)与这些患者的生存期缩短和转移的发生联系起来。P21和GADD45编码区未发现突变，提示P53基因产物的突变是其致癌的主要原因。P53、MDM2和p21在NSCLC中的异质性表达提示了多种反式激活或抑制反式激活因子导致肿瘤发生的机制。