Unopposed c-MYC expression in benign prostatic epithelium causes a cancer phenotype
Unopposed c-MYC expression in benign prostatic epithelium causes a cancer phenotype
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DOI：
10.1002/pros.20200
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发表时间：
2005-06-01
期刊：
影响因子：
2.8
通讯作者：
Hayward, SW
中科院分区：
文献类型：
--
作者：
Williams, K;Fernandez, S;Hayward, SW
背景我们试图利用人前列腺上皮细胞培养物建立一种新的前列腺癌发生的体内模型。人类前列腺癌经常在8 q24扩增子中显示DNA扩增，这导致c-MYC基因拷贝数增加，这一发现表明c-MYC在人类前列腺癌发生中发挥作用。此外，在转基因小鼠模型中c-MYC的过度表达导致前列腺癌的发生。我们利用逆转录病毒将外源DNA整合到人前列腺上皮（huPrE）中的能力，产生过表达c-MYC原癌基因的细胞系。这些细胞与诱导的大鼠尿生殖窦间充质重组，并移植到免疫功能低下的啮齿动物宿主的肾包膜下。所得组织显示与低分化人前列腺腺癌一致的表型。肿瘤生长迅速，增殖指数高。肿瘤中的肿瘤细胞同时表达雄激素受体（AR）和前列腺特异性抗原（PSA），这两种都是人类前列腺癌的特征性标志物。人前列腺上皮细胞过表达c-MYC的微阵列分析鉴定了大量差异表达的基因，其中一些已被认为是具有myc过表达的人类癌症亚组的特征。通过蛋白质印迹分析证实了具体的实例，包括c-Myb的上调和PTEN表达的降低。使用未感染的huPrE或使用表达绿色荧光蛋白标签的空载体感染的huPrE细胞的对照移植物产生分化良好的良性前列腺腺导管。通过使用逆转录病毒感染策略，然后进行组织重组，我们已经创建了一个人前列腺癌模型，该模型表明c-MYC基因足以诱导致癌作用。(c)2004 Wiley-Liss，Inc.
BACKGROUND. We have sought to develop a new in vivo model of prostate carcinogenesis using human prostatic epithelial cell cultures. Human prostate cancers frequently display DNA amplification in the 8q24 amplicon, which leads to an increase in the copy number of the c-MYC gene, a finding that suggests a role for c-MYC in human prostate carcinogenesis. In addition overexpression of c-MYC in transgenic mouse models results in prostatic carcinogenesis.METHODS. We took advantage of the ability of retroviruses to integrate foreign DNA into human prostatic epithelium (huPrE) to generate cell lines that overexpress the c-MYC protooncogene. These cells were recombined with inductive rat urogenital sinus mesenchyme and grafted beneath the renal capsule of immunocompromised rodent hosts.RESULTS. The resultant tissue displayed a phenotype consistent with a poorly differentiated human prostatic adenocarcinoma. The tumors were rapidly growing with a high proliferative index. The neoplastic cells in the tumor expressed both androgen receptors (AR) and prostate-specific antigen (PSA), both characteristic markers of human prostate cancers. Microarray analysis of human prostatic epithelial cells overexpression c-MYC identified a large number of differentially expressed genes some of which have been suggested to characterize a subset of human cancers that have myc overexpression. Specific examples were confirmed by Western blot analysis and include upregulation of c-Myb and decreased expression of PTEN. Control grafts using either uninfected huPrE or using huPrE cells infected using an empty vector expressing a green fluorescent protein tag gave rise to well differentiated benign prostatic glandular ducts.CONCLUSIONS. By using a retroviral infection strategy followed by tissue recombination we have created a model of human prostate cancer that demonstrates that the c-MYC gene is sufficient to induce carcinogenesis. (c) 2004 Wiley-Liss, Inc.