TRANSGENIC MODELS--COOPERATION OF C MYC AND GROWTH FACTORS IN TUMORIGENESIS

转基因模型--C MYC和生长因子在肿瘤发生中的合作

• 批准号: 5201568
• 负责人: S S THORGEIRSSON
• 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/5201568
• 关键词: apoptosis; carcinogenesis; cell growth regulation; cellular oncology; disease /disorder model; gene expression; gene interaction; genetically modified animals; growth factor; hepatocellular carcinoma; hepatocyte growth factor; laboratory mouse; model design /development; neoplastic process; oncogenes; preneoplastic state; protein tyrosine kinase; protooncogene; transforming growth factors

To investigate the interaction of the nuclear oncogene c-myc with different growth factors acting via tyrosine kinase kinase receptors, we have analyzed the mechanism of hepatocarcinogenesis in three lines of transgenic mice overexpressing c-myc alone and coexpressed with transforming growth factor-alpha (TGFalpha) or hepatocyte growth factor (HGF). We demonstrate that sustained overexpression of c-myc in the liver leads to cancer through highly abnormal cell proliferation. Coexpression of TGFalpha dramatically accelerated c-myc-associated hepatocarcinogenesis and provided a selective growth advantage to the tumor cells by both increasing their proliferation and reducing their susceptibility to apoptosis. Clusters of cells in preneoplastic lesions produced higher levels of TGFalpha suggesting a mechanism for clonal growth. Although there was high coexpression of TGFbeta1 and urokinase-plasminogen activator (uPA) in the liver of c-myc/TGFalpha mice, the neoplastic tissues showed very low levels of BAX and TGFbeta receptor type I and II, all proteins related to apoptosis and growth inhibition. Despite high levels of p53 and p21/WAF1, the tumors overexpressed cyclin D1, PCNA, cyclin B, cdc2 and showed changes in the phosphorylation state of Rb protein, suggesting a lack of checkpoints in the cell cycle as a cause of abnormal cell proliferation. Tumors arising in c-myc and c-myc/TGFalpha displayed increased levels of endogenous TGFalpha, confirming the importance of this growth factor for tumor promotion. In contrast, coexpression of HGF and c-myc in double transgenic mice decreased c-myc-induced cell proliferation, delayed the neoplastic process, and prevented malignant conversions of the preneoplastic lesions. These lesions exhibited decreased levels of HGF receptor, implying a mechanism of escape from the HGF modulation. Furthermore, tumor promotion by phenobarbital (PB) was completely inhibited in the c-myc/HGF transgenic line, while PB was an effective tumor promoter in the c-myc single transgenic mice. Taken together, our data indicate that HGF may act as liver tumor suppressor by preventing the growth of initiated hepatocytes.

研究核癌基因c-myc与 不同的生长因子通过酪氨酸激酶激酶受体起作用，我们 分析了三个品系肝癌发生的机制， 单独过表达c-myc并共表达c-myc的转基因小鼠 转化生长因子-α（TGF α）或肝细胞生长因子 （HGF）。 我们证明了在乳腺癌中持续的c-myc过表达， 肝脏通过高度异常的细胞增殖导致癌症。 TGF α的共表达显著促进了c-myc相关的 肝癌发生，并提供了选择性生长优势， 通过增加肿瘤细胞的增殖和减少其 细胞凋亡的易感性。 癌前病变中的细胞簇 产生了更高水平的TGF α，这表明了克隆的机制。 增长 虽然TGF β 1和TGF β 2的高共表达， c-myc/TGF α肝内尿激酶-纤溶酶原激活物（uPA） 在小鼠中，肿瘤组织显示出非常低水平的BAX和TGF β I型和II型受体，所有与凋亡和生长相关的蛋白质 抑制作用 尽管p53和p21/WAF 1水平高， cyclin D1、PCNA、cyclin B、cdc 2过表达， Rb蛋白的磷酸化状态，这表明缺乏检查点， 细胞周期作为异常细胞增殖的原因。 产生的肿瘤 在c-myc和c-myc/TGF α中， TGF α，证实了这种生长因子对肿瘤的重要性 推广. 与此相反，HGF和c-myc共表达的双 转基因小鼠降低c-myc诱导的细胞增殖，延迟 肿瘤过程，并防止恶性转化的 癌前病变 这些病变显示HGF水平降低 受体，暗示逃避HGF调节的机制。 此外，苯巴比妥（PB）的肿瘤促进作用完全被证实。 在c-myc/HGF转基因株系中， c-myc单转基因小鼠中的肿瘤启动子。 总的来说，我们的 数据表明，HGF可能通过预防肝肿瘤的发生而起到肝肿瘤抑制剂的作用。 启动肝细胞的生长。