Development of gene diagnosis and therapy for endometrial cancers.

将来自正常成纤维细胞的1号染色体导入HHUA子宫内膜癌可抑制致瘤性。这种致瘤性抑制伴随着显著的形态学改变。微细胞杂交种的特点是细胞内形成肌动蛋白，肌动蛋白和血管蛋白过度积累。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1号或18号染色体已被证明可诱导人子宫内膜癌细胞衰老。这表明，在某些人子宫内膜癌细胞系中，两种不同的正常染色体诱导衰老，这与该细胞系中多条衰老途径失活的观点是一致的。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的发生，我们在42个癌中寻找该基因的核苷酸序列变化。在17p上有LOH的两种癌症在保留的等位基因中含有突变的p53基因。一个p53基因突变的物种含有17q缺失，但对17p上的LOH没有信息。在其余的癌症中也发现了P53基因突变，尽管没有检测到17p缺失。考虑到这4种癌症的临床分期，提示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基因的表达，以确定子宫内膜癌中18q的重要基因。肿瘤可能涉及DCC基因定位的18q21.3带内或附近的区域。此外，DCCmRNA表达改变的发生率较高（14/28,50%）。这些数据表明，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。

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.