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Development of gene diagnosis and therapy for endometrial cancers.

子宫内膜癌基因诊断和治疗的发展。

基本信息

批准号：
05454453
负责人：
WAKE Norio
金额：
$ 4.16万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

Introduction of a single chromosome 1 derived from normal fibroblasts into HHUA endometrial carcinoma resulted in suppression of tumorigenicity. This tumorigenic suppression was accompanied by remarkable morphological changes. The microcell hybrids were characterized by intracellular actin formation and an excessive accumulation of actin and vinculin. The latter was a result of increased stabilization of the proteins.Introduction of a human chromosome 1 or 18 by microcell-mediated chromosome transfer has been shown to induce senescence of human endometrial cancer cells. This suggested that two different normal chromosomes induce senescence in the some human endometrial carcinoma cell line, being compatible with the idea that multiple pathways to senescence are inactivated in this cell line.Allelic losses on chromosome 17p and 18q have been associated with human endometrial carcinomas. In order to confirm involveament of the p53 gene in endometrial carcinogenesis, we searched for nucleotide sequence change in this gene in 42 carcinomas. Two cancers with LOH on 17p contained a mutant p53 gene in the allele that was retained. One speciwen with a p53 gene mutation contained a 17q deletion but was uninformative for LOH on 17p. P53 gene mutation was also noted in the remaining cancer, though the 17p deletion was not detected. Consideration of clinical stages in these 4 cancers suggested that with p53 gene mutations were involved in endometrial cancer progression.We analyzed LOH at 3 loci on 18q and DCC gene expression to define the gene of importance on 18q in endometrial cancers. The tumors possibly involved the region within or near the 18q 21.3 band where the DCC gene was localized. Moreover, the incidence of altered DCCmRNA expression was high (14/28,50%). The data suggested that the targer for LOH on 18q seen in endometrial cancers was the DCC gene, and that inactivation of this gene might be critical for the development of most endometrial cancers.

将源自正常成纤维细胞的单条 1 号染色体引入 HHUA 子宫内膜癌可抑制致瘤性。这种致瘤抑制伴随着显着的形态变化。微细胞杂交体的特征是细胞内肌动蛋白形成以及肌动蛋白和纽蛋白的过度积累。后者是蛋白质稳定性增强的结果。通过微细胞介导的染色体转移引入人类 1 号或 18 号染色体已被证明可以诱导人类子宫内膜癌细胞的衰老。这表明两条不同的正常染色体在某些人类子宫内膜癌细胞系中诱导衰老，这与该细胞系中多种衰老途径失活的观点相一致。染色体 17p 和 18q 上的等位基因丢失与人类子宫内膜癌有关。为了证实p53基因参与子宫内膜癌发生，我们在42种癌症中寻找该基因的核苷酸序列变化。两种 17p 上存在 LOH 的癌症在保留的等位基因中含有突变的 p53 基因。一个具有 p53 基因突变的样本包含 17q 缺失，但没有提供 17p 上的 LOH 信息。在剩余的癌症中也发现了 P53 基因突变，但未检测到 17p 缺失。对这 4 种癌症的临床分期的考虑表明，p53 基因突变与子宫内膜癌的进展有关。我们分析了 18q 上 3 个位点的 LOH 和 DCC 基因表达，以确定子宫内膜癌中 18q 上的重要基因。肿瘤可能涉及 DCC 基因所在的 18q 21.3 带内或附近的区域。此外，DCCmRNA表达改变的发生率很高(14/28，50%)。数据表明，子宫内膜癌中 18q 上 LOH 的靶标是 DCC 基因，该基因的失活可能对大多数子宫内膜癌的发展至关重要。