Inductible mouse models for oral cancer

口腔癌是第七大常见的癌症，在美国每年有8,000人死于口腔癌 全球128，000人。与其他肿瘤类型相似，口腔癌的形成被广泛接受， 癌症是一个多步骤的过程，是遗传变异积累的结果。高频 在某些基因中发现的遗传和表观遗传改变强烈暗示了THQ的因果作用 口腔癌的发展。我们的长期目标是产生携带inducibh的转基因小鼠， 基因改变，密切模仿一些最常见的突变，发现在人类癌症的或 腔尽管在口腔癌患者中已经报道了大量的基因改变， 不同的分子途径似乎是突变的主要靶点，即p53，视网膜母细胞瘤， (Rb)和表皮生长因子受体（EGFR）信号通路。因此，基因改变 在口腔癌中最常见的包括EGFR过表达、p53突变（如获得性 功能p53 R175 H）和INK 4a/ARF基因座的失活，其至少部分地作为负调控因子发挥作用。 Rb通路的调节剂。我们假设这些在口腔癌中发病率高的突变 患者在口腔癌的发展中起着因果作用。为了验证这一假设，我们将使用 诱导系统，以产生表现出p53突变、EGFR过表达或 INK 4a/ARF基因座仅在口腔中失活。这些模型有几个优点， 传统的转基因/敲除模型：突变可以靶向组织的限制区域 并且可以选择肿瘤起始的时刻。因此，它们将密切模仿散发性病灶 在人类肿瘤中发现的体细胞突变的积累。这些小鼠模型不仅对 更好地了解口腔癌发展的分子机制，也可以作为临床前模型， 测试用于预防和干预口腔癌的治疗剂。

Oral cancer is the seventh most common form o_ cancer and causes 8,000 deaths in the United States each year and 128,000 worldwide. Similar to other tumor types, it is widely accepted that the formation of oral cancer is a multi-step process that results from the accumulation of genetic alterations. The high frequency of genetic and epigenetic alterations found in certain genes strongly suggests a causal role in thq development of oral cancer. Our long-term objective is to generate transgenic mice carrying inducibh genetic alterations that closely mimic some of the most common mutations found in human cancer of the or_ cavity. Although a large number of genetic alterations have been reported in oral cancer patients, three different molecular pathways seem to be the major targets of mutations, namely the p53, retinoblastoma (Rb) and Epidermal Growth Factor Receptor (EGFR) signaling pathways. Accordingly, the gene alterations most frequently found in oral cancer include EGFR overexpression, p53 mutations (such as the gain-of- function p53R175H) and inactivation of the INK4a/ARF locus, which functions at least in part as a negative regulator of the Rb pathway. We hypothesize that these mutations that have a high incidence in oral cancer patients play a causal role in the development of cancer of the oral cavity. To test this hypothesis we will use an inducible system to generate mouse models that exhibit p53 mutations, EGFR overexpression or inactivation of the INK4a/ARF locus only in the oral cavity. These models have several advantages over conventional transgenic/knockout models: the mutation can be targeted to a restricted area of the tissue and the moment of tumor initiation can be chosen. Therefore, they will closely mimic the sporadic focal accumulation of somatic mutations found in human tumors. These mouse models will be useful not only to better understand the molecular mechanisms of oral cancer development, but also as preclinical models for testing therapeutic agents for prevention and intervention of oral cancer.