Targeting the WntBeta-catenin Pathway in Liver Cancer

描述（由申请人提供）：肝癌是世界范围内癌症死亡的主要原因，通常与暴露于亚硝胺和黄曲霉毒素等环境毒素有关。这种疾病的分子发病机制尚不完全清楚，因此限制了成功治疗甚至预防其发展的能力。一个与肝癌发生有关的信号通路是Wnt/（3-连环蛋白）通路。在肝脏肿瘤标本中观察到的许多突变以这样或那样的方式导致该途径的异常激活，包括各种丝氨酸和苏氨酸残基的突变，这些残基是与蛋白质蛋白酶体降解相关的重要磷酸化位点。我们假设，这种3-连环蛋白的稳定为肝细胞在毒素暴露后导致的发育不良生长条件下提供了显著的生长优势。此外，我们相信从药理学上靶向这一途径可以预防和减缓肝癌的发展。为了验证这一假设，我们开发了一种转基因小鼠系，在丝氨酸45位点（最终降解的关键磷酸化位点之一）过度表达3-连环蛋白。在本研究的第一个目的中，这些小鼠将暴露于二乙基亚硝胺（DEN），一种用于小鼠的常见肝癌原，以检查肝癌的发展。我们还将研究(3-catenin抑制在该模型中用于化学预防和/或化疗的潜力。在第二个目标中，我们将探索Hep-S45D-TG小鼠的肝脏兼性祖细胞卵圆细胞的激活，因为它们具有作为癌症干细胞的潜在作用。再一次，我们将利用3-连环蛋白抑制来检测针对这种干细胞群的治疗潜力。确定肝癌发展和癌症干细胞活化的关键分子可能对患有这种高死亡率疾病的患者的治疗产生重大影响。肝癌是一种使人衰弱的疾病，是全世界癌症死亡的主要原因之一。确定这种疾病的潜在原因，异常的3-连环蛋白活性，以及针对这一原因的适用性，将对肝癌治疗产生重大影响。

DESCRIPTION (provided by applicant): Liver cancer is a leading cause of cancer mortality worldwide, frequently being associated with exposure to environmental toxins such as nitrosamines and aflatoxin. The molecular pathogenesis of this disease is not yet fully understood, thus limiting the ability to successfully treat or even prevent its development. One signaling pathway that has been implicated in hepatocarcinogenesis is the Wnt/(3-catenin pathway. Many mutations observed in liver tumor specimens in one way or another lead to aberrant activation of this pathway, including mutations in various serine and threonine residues which are important phosphorylation sites associated with the protein's proteasomal degradation. We hypothesize that such stabilization of 3- catenin provides the hepatocyte with a significant growth advantage during dysplastic growth conditions that result following toxin exposure. Furthermore, we believe that targeting this pathway pharmacologically can prevent and slow the development of liver cancer. To test this hypothesis we have developed a transgenic mouse line overexpressing (3-catenin mutated at Serine 45, one of the key phosphorylation sites for eventual degradation. In the first aim of this study, these mice will be exposed to diethylnitrosamine (DEN), a common hepatocarcinogen used in mice, to examine the development of liver cancer. We will also examine the potential of (3-catenin suppression in this model for chemoprevention and/or chemotherapy. In the second aim, we will explore activation of the facultative progenitor cells of the liver, oval cells, in Hep-S45D-TG mice given their potential role as cancer stem cells. Once again, we will utilize 3-catenin suppression to examine treatment potential for targeting this stem cell population. The identification of a key molecular player in liver cancer development and cancer stem cell activation could have a significant impact on therapy for patients who suffer from this high mortality disease. Liver cancer is a debilitating disease which is one of the leading causes of cancer death worldwide. The identification of a potential cause for this disease, aberrant 3-catenin activity, and the applicability of targeting this cause will have a significant impact on liver cancer therapy.