Molecular Genetics of Liver Cancers

摘要 肝癌是一种致命的疾病，缺乏任何有效的治疗选择。这背后的分子遗传学 致命的恶性疾病仍然鲜为人知。河马肿瘤抑制级联反应是一种进化 控制器官大小、组织再生、干细胞自我更新和肿瘤的保守途径 发展。最近的遗传学研究支持河马通路在肝癌中的重要性 发展。然而，YAP和TAZ这两个转录共激活因子的确切功能 河马蛋白水解酶的下游，以及它们如何与其他致癌途径相互作用 致癌机制尚未确定。在我们最近的研究中，我们发现YAP和TAZ都是高度 在人类肝癌样本的子集中表达。重要的是，我们发现，虽然YAP或TAZ单独是 YAP或TAZ过表达不能在体内诱导肝肿瘤形成与激活的AKT协同作用 促进小鼠肝癌发生的信号。肿瘤细胞也表现出细胞增殖的增加。 作为激活的Notch和Wnt/β-连环蛋白通路。此外，我们发现YAP和TAZ都被激活 在多种小鼠肝肿瘤模型中，包括AKT/RAS或c-Myc癌基因诱导的肝癌。 过表达Lats2，抑制核定位，促进YAP或TAZ的降解 抑制AKT/RAS和c-Myc诱导的小鼠肝癌发生，支持河马的关键作用 癌基因诱导的肝肿瘤发生的调控途径。在这项竞争性续订申请中，我们 将系统地描述YAP和TAZ在肝癌发展过程中的功能作用。我们 提出三个目标。在第一个目标中，我们将阐明加速肝脏的分子机制。 AKT/YAP或AKT/TAZ共表达诱导肿瘤发生。在目标二中，我们将定义角色 YAP和TAZ在AKT/RAS诱导的肝肿瘤发生中的作用在目标三中，我们将描述 YAP和TAZ在c-Myc诱导的肝癌发生中的作用总而言之，在建议的 应用程序，我们将应用复杂的小鼠遗传方法，目的是揭示 YAP和TAZ转录共激活因子在肝癌发生中的意义这项研究还将 为关键致癌基因之间的遗传和生化串扰提供新的机制洞察力 包括YAP/TAZ、AKT/mTOR、Wnt/β-catenin、Notch和c-Myc在内的通路在肝癌发生中的作用 发展。这项研究可能会提供强有力的证据来支持小分子或 以siRNA为基础的针对YAP或TAZ的治疗作为肝癌的新治疗策略。

Abstract Liver Cancer is a deadly disease, lacking any effective treatment options. Molecular genetics underlying this deadly malignancy remains poorly understood. The Hippo tumor suppressor cascade is an evolutionally conserved pathway that controls organ size, tissue regeneration, stem cell self-renewal, and tumor development. Recent genetic studies support the importance of Hippo pathway during liver cancer development. However, the precise functional role of Yap and TAZ, the two transcriptional co-activators downstream of Hippo kinases, and how they interact with other onocgenic pathways during hepatic carcinogenesis have not been characterized. In our recent studies, we found that Yap and TAZ are both highly expressed in a subset of human liver cancer samples. Importantly, we found that while Yap or TAZ alone is unable to induce liver tumor formation in vivo, overexpression of Yap or TAZ synergizes with activated AKT signaling to accelerate hepatic carcinogenesis in mice. The tumor cells show increased cell proliferation as well as activated Notch and Wnt/¿-catenin pathways. Furthermore, we found that both Yap and TAZ are activated in multiple mouse liver tumor models, including HCC induced by AKT/Ras or c-Myc oncogenes. Overexpression of Lats2, which inhibits nuclear localization and promotes degradation of Yap or TAZ, strongly inhibited AKT/Ras and c-Myc induced hepatic carcinogenesis in mice, supporting a critical role of Hippo pathway in regulating oncogene induced liver tumor development. In this competing renewal application, we will systematically characterize the functional roles of Yap and TAZ during liver cancer development. We propose three aims. In Aim One, we will elucidate the molecular mechanisms underlying accelerated liver tumor development induced by the co-expression of AKT/Yap or AKT/TAZ. In Aim Two, we will define the role of Yap and TAZ in AKT/Ras induced liver tumor development. And in Aim Three, we will characterize the functional contribution of Yap and TAZ in c-Myc induced hepatic carcinogenesis. Altogether, in the proposed application, we will apply sophisticated mouse genetic approaches with the goal to uncover the functional significance of Yap and TAZ transcriptional co-activators during hepatic carcinogenesis. The study will also provide novel mechanistic insight into the genetic and biochemical crosstalk among the key oncogenic pathways, including Yap/TAZ, AKT/mTOR, Wnt/¿-catenin, Notch and c-Myc cascades during liver cancer development. The study will likely provide strong evidence to support the development of small molecules or siRNA based therapeutics against Yap or TAZ as novel treatment strategies for liver cancer.