Drivers of gastric pre-neoplasia

项目总结/摘要 胃癌是世界范围内癌症相关死亡的最常见原因之一。它是在一个 从癌前化生到癌性异型增生的致癌级联的顺序进展， 腺癌然而，导致致癌转变的致癌驱动因子或主调节因子 癌前病变和癌变之间的关系是不确定的。此前的调查显示， 在高达40%的胃癌患者中观察到Ras活性，并表明Ras在胃癌患者中的活化。 胃癌可促进化生向异型增生和癌的进展。我们以前的结果 描述了主细胞中的Kras激活可以快速发展化生和侵袭性化生， 发育不良的腺体因此，这些研究表明，Kras激活可能是胃溃疡的驱动因素， 胃癌的发生可能与癌前病变和主细胞有关。然而， 至于Kras激活是否是控制异型增生致癌过程的关键致癌驱动因素， 到腺癌。此外，尽管Sox转录因子激活在致癌Kras基因表达后的作用， 在其他胃肠道癌症中已经充分研究了这种激活，但没有研究表明这种活性是否 对于化生的发展是重要的，或者与胃癌发生中的Ras活化有关。 因此，我们假设Kras激活是胃癌发生和化生的驱动因素， 通过上调作为Kras下游效应子的Sox 9，可以控制肿瘤的发生和发展 信号通路我们提出了两个具体的目标，以阐明更深入的理解细胞机制 和胃癌发生的事件，使用一种新的诱导驱动小鼠模型，这是一个胃-和 主要细胞特异性驱动小鼠等位基因。首先，我们将定义Kras激活的致癌作用， 胃癌发生过程中活性Kras诱导细胞的谱系贡献。第二，我们将评估 Sox 9转录因子作为化生发展的假定主调节因子的功能作用， 进展我们提出的研究不仅将确定胃癌的起源细胞， 胃癌发生发展过程中Kras激活的致癌潜力和调控机制。 因此，我们从这项拟议研究中获得的结果将为临床前信息提供见解， 治疗干预或确定新的药物靶点，通过调节转录调控的关键 胃癌患者的饮食习惯

PROJECT SUMMARY / ABSTRACT Gastric cancer is one of the most common causes of cancer-related death worldwide. It develops in a sequential progression of a carcinogenic cascade from pre-cancerous metaplasia to cancerous dysplasia and adenocarcinoma. However, oncogenic drivers or master regulators which lead to carcinogenic transition between pre-cancerous and cancerous stages are uncertain. Previous investigations have noted that Kras activity is observed in up to 40% of patients with gastric cancer and have suggested that Ras activation in gastric cancer may promote the progression of metaplasia toward dysplasia and cancer. Our previous results described that Kras activation in chief cells can rapidly develop metaplasia and invasive metaplasia with dysplastic glands. These studies therefore imply that Kras activation might be a driving factor of gastric carcinogenesis and chief cells might be an origin of gastric cancer. However, there is a clear knowledge gap as to whether Kras activation is a critical oncogenic driver which controls the carcinogenic process of dysplasia to adenocarcinoma. Also, while roles of Sox transcription factor activation following the oncogenic Kras activation have been well-studied in other GI tract cancers, no studies have addressed whether such activities are important for metaplasia development or are associated with Ras activation in gastric carcinogenesis. We have therefore hypothesized that Kras activation is a driver of gastric carcinogenesis and metaplastic development and progression can be controlled by upregulation of Sox9 as a downstream effector of Kras signaling pathway. We propose two specific aims to elucidate a deeper understanding of cellular mechanisms and events of gastric carcinogenesis using a novel inducible driver mouse model, which is a stomach- and chief cell-specific driver mouse allele. First, we will define the oncogenic roles of Kras activation and the lineage contribution of active Kras-induced cells during gastric carcinogenesis. Second, we will assess functional roles of Sox9 transcription factor as a putative master regulator of metaplasia development and progression. Our proposed study will not only define the cells of origin for gastric cancer, but also determine the oncogenic potential and regulatory mechanisms of Kras activation during gastric cancer development. Consequently, our results from this proposed study would provide insights in pre-clinical information to design therapeutic interventions or to identify novel druggable targets by regulating transcriptional regulation of key factors in patients with gastric cancer.