Molecular Genetics of Liver Cancers

描述(申请人提供)：肝癌是一种致命的疾病，缺乏任何有效的治疗选择。这种致命的恶性肿瘤背后的分子遗传学仍然知之甚少。河马肿瘤抑制级联反应是一条进化上保守的途径，控制器官大小、组织再生、干细胞自我更新和肿瘤发展。最近的遗传学研究支持河马通路在肝癌发生发展中的重要性。然而，河马蛋白激酶下游的两个转录共激活因子YAP和TAZ的确切功能以及它们在肝细胞癌发生过程中如何与其他致癌途径相互作用尚不清楚。在我们最近的研究中，我们发现YAP和TAZ在人类肝癌样本的子集中都高度表达。重要的是，我们发现，虽然YAP或TAZ单独不能在体内诱导肝癌的形成，但YAP或TAZ的过度表达与激活的AKT信号协同作用，加速小鼠肝癌的发生。肿瘤细胞表现出细胞增殖增加以及Notch和Wnt/�-Catenin通路的激活。此外，我们发现YAP和TAZ在多种小鼠肝肿瘤模型中都被激活，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，强烈抑制AKT/RAS和c-Myc诱导的小鼠肝癌发生，支持Hippo途径在调节癌基因诱导的肝癌发生中的关键作用。在这个竞争性的更新应用中，我们将系统地描述YAP和TAZ在肝癌发展过程中的功能作用。我们提出了三个目标。在第一个目标中，我们将阐明AKT/YAP或AKT/TAZ共表达促进肝癌发生的分子机制。在第二个目标中，我们将确定YAP和TAZ在AKT/RAS诱导的肝肿瘤发生中的作用。在第三个目标中，我们将研究YAP和TAZ在c-Myc诱导的肝细胞癌发生中的作用。总之，在拟议的应用中，我们将应用复杂的小鼠遗传学方法，目的是揭示YAP和TAZ转录共激活因子在肝癌发生过程中的功能意义。这项研究还将从新的机制上深入了解肝癌发展过程中关键的致癌途径之间的遗传和生化串扰，包括YAP/TAZ、AKT/MTOR、WNT/�-Catenin、Notch和c-Myc。这项研究可能会提供强有力的证据，支持以小分子或siRNA为基础的针对YAP或TAZ的疗法作为肝癌的新治疗策略。

DESCRIPTION (provided by applicant): 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.