Bayer Schering Pharma AG, Global Drug Discovery, Berlin, Germany.
Oncogene. 2010 Apr 15;29(15):2205-16. doi: 10.1038/onc.2009.507. Epub 2010 Jan 25.
Oncolytic Newcastle disease virus (NDV) replicates selectively in most human tumor cells but not in normal cells. The relationship between tumorigenesis and the selective susceptibility of most tumor cells to oncolytic NDV replication is poorly understood. A multistage skin carcinogenesis model derived from non-tumorigenic HaCaT cells was used to systematically investigate the molecular mechanisms involved in the oncolytic NDV-sensitivity associated with tumorigenic transformation. No significant differences in interferon signaling were observed between the virus-sensitive tumor cells and the virus-resistant non-tumorigenic parental cells. Oncogenic H-Ras, which had been used for tumorigenic transformation, was shown to be necessary for virus replication but was not sufficient to render cells susceptible to NDV replication. By using an siRNA screening approach to search for virus-sensitizing genes in the tumorigenic cells, we could identify the small GTPase Rac1 as an oncogenic protein that is essential for NDV replication and anchorage-independent growth in tumorigenic cells. Furthermore, Rac1 expression was sufficient to render non-tumorigenic cells susceptible to NDV replication and to oncolytic cytotoxicity. This study establishes Rac1 as a link between tumorigenesis and oncolytic virus sensitivity in the HaCaT multistage skin carcinogenesis model.
溶瘤性新城疫病毒（NDV）选择性地在大多数人类肿瘤细胞中复制，但不在正常细胞中复制。肿瘤发生与大多数肿瘤细胞对溶瘤性 NDV 复制的选择性易感性之间的关系尚未得到很好的理解。本研究采用源自非致瘤性 HaCaT 细胞的多阶段皮肤致癌模型，系统地研究了与肿瘤发生转化相关的溶瘤性 NDV 敏感性所涉及的分子机制。在病毒敏感的肿瘤细胞和病毒抗性的非致瘤性亲本细胞之间，干扰素信号没有明显差异。已用于致瘤转化的致癌 H-Ras 被证明是病毒复制所必需的，但不足以使细胞对 NDV 复制敏感。通过使用 siRNA 筛选方法在致瘤细胞中寻找病毒敏感基因，我们可以鉴定出小 GTPase Rac1 是一种致癌蛋白，它是 NDV 复制和致瘤细胞中锚定非依赖性生长所必需的。此外，Rac1 的表达足以使非致瘤细胞对 NDV 复制和溶瘤细胞毒性敏感。本研究在 HaCaT 多阶段皮肤致癌模型中确立了 Rac1 作为肿瘤发生和溶瘤病毒敏感性之间的联系。
