IN VITRO STUDIES OF HUMAN MESOTHELIAL CELL CARCINOGENESIS

人间皮细胞致癌的体外研究

• 批准号: 3752700
• 负责人: B I GERWIN
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752700
• 关键词: carcinogenesis; cell line; cellular oncology; gene expression; gene induction /repression; genetic promoter element; growth factor receptors; human genetic material tag; human tissue; mesothelioma; neoplasm /cancer genetics; platelet derived growth factor; receptor expression; transcription factor; tumor antigens

Cell lines from human mesotheliomas have been shown to express the platelet-derived growth factor (PDGF)-A gene product, while normal human mesothelial cells do not. A T-antigen immortalized human mesothelial cell overexpressing PDGF-A chain was shown to be tumorigenic. Analysis of the receptor-ligand interactions in this cell line, human mesothelioma cell lines and normal and T-antigen expressing, non-tumorigenic human mesothelial cells aims to identify mechanisms of carcinogenesis. Platelet-derived growth factor receptor (PDGFR)-alpha but not PDGFR-beta expression is down regulated in mesothelioma as compared to normal mesothelial cells. A model human mesothelial cell in which PDGFR-alpha is expressed has been identified. This system will be utilized to investigate the transcriptional control of this receptor and its relevance to pathogenesis of the disease. In an attempt to identify inactivated tumor suppressor pathways, mesothelioma cell lines in which the p53 gene had been shown to be wild type or mutant were studied for expression of the MDM2 gene product. Results of these analyses indicated that overexpression of MDM2 was not a frequent occurrence in mesothelioma cell lines. However, cell lines with p53 mutations contained the lowest levels of MDM2. It has been shown previously that mesothelioma cells contain normal levels of the Rb protein. Recent experiments show that five of five mesothelioma cell lines have homozygous deletions of p16, a candidate tumor suppressor gene localized to chromosome 9p21-22, a site whose loss is commonly associated with mesothelioma. Deletion of the function of this gene would block the G1 arrest induced by Rb, inactivating this important check on cell division and error-prone DNA synthesis.

来自人类间皮瘤的细胞系已被证明表达 血小板衍生生长因子（PDGF）-一种基因产物，而正常人 间皮细胞则不然。 T抗原永生化人间皮细胞 过度表达 PDGF-A 链的细胞被证明具有致瘤性。 分析 人类间皮瘤细胞系中受体-配体相互作用的研究 细胞系以及表达正常和 T 抗原的非致瘤人类 间皮细胞旨在确定致癌机制。 血小板衍生生长因子受体 (PDGFR)-α，但不是 PDGFR-β 与正常人相比，间皮瘤中的表达下调 间皮细胞。 人类间皮细胞模型，其中 PDGFR-α 表示已被识别。 该系统将用于 研究该受体及其转录控制 与疾病发病机制的相关性。 试图识别 失活的肿瘤抑制途径，间皮瘤细胞系，其中 p53基因已被证明是野生型或已研究突变型 MDM2基因产物的表达。 这些分析的结果表明 MDM2 过度表达在间皮瘤中并不常见 细胞系。然而，具有 p53 突变的细胞系含有最低的 MDM2 水平。 此前已有研究表明，间皮瘤细胞 含有正常水平的 Rb 蛋白。 最近的实验表明 五分之五的间皮瘤细胞系具有 p16 纯合缺失， 位于染色体 9p21-22 的候选肿瘤抑制基因，一个位点 其损失通常与间皮瘤有关。 删除 该基因的功能将阻断 Rb 诱导的 G1 停滞， 使细胞分裂和容易出错的 DNA 的这一重要检查失活 合成。