Targeting the WntBeta-catenin Pathway in Liver Cancer

靶向肝癌中的 WntBeta-catenin 通路

• 批准号: 7485471
• 负责人: Michael D Thompson
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485471
• 关键词: Address; Affect; Aflatoxins; Albumins; Appearance; Appendix; Attenuated; Binding; Cancer Etiology; Cellular biology; Cessation of life; Chemoprevention; Condition; Cyclin D1; Data; Development; Diethylnitrosamine; Disease; Enhancers; Etodolac; Exhibits; Exposure to; Gene Mutation; Genes; Glutamate-Ammonia Ligase; Growth; Hepatic; Hepatocarcinogenesis; Hepatocyte; Histology; Interferons; Lead; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Molecular; Molecular Biology; Morphology; Mus; Mutate; Mutation; Natural regeneration; Nitrosamines; Nuclear; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Play; Population; Prevention; Primary carcinoma of the liver cells; Protein Overexpression; Proteins; Range; Rate; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Specimen; Stem cells; Testing; Threonine; Toxic Environmental Substances; Toxin; Transgenic Mice; Up-Regulation; Wild Type Mouse; Zalcitabine; adenoma; base; c-myc Genes; cancer stem cell; cancer therapy; carcinogenesis; chemotherapy; human FZD7 protein; mortality; novel; outcome forecast; oval cell; prevent; progenitor; promoter; receptor; response; tumor; tumorigenesis

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.

描述（由申请人提供）：肝癌是全球癌症死亡率的主要原因，通常与暴露于环境毒素（如亚硝胺和黄曲霉毒素）有关。这种疾病的分子发病机制尚未完全了解，因此限制了成功治疗甚至预防其发展的能力。一种与肝癌发生有关的信号通路是Wnt/β-连环蛋白通路。在肝肿瘤标本中观察到的许多突变以一种或另一种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中的突变，这些残基是与蛋白质的蛋白酶体降解相关的重要磷酸化位点。我们假设，这种稳定的3-连环蛋白提供了一个显着的生长优势，在发育不良的生长条件下，导致毒素暴露的肝细胞。此外，我们认为，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，我们开发了一种过表达β-连环蛋白的转基因小鼠品系，该蛋白在丝氨酸45处突变，丝氨酸45是最终降解的关键磷酸化位点之一。在本研究的第一个目标中，这些小鼠将暴露于二乙基亚硝胺（DEN），这是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β-连环蛋白抑制在该模型中用于化学预防和/或化学疗法的潜力。在第二个目标中，我们将探索Hep-S45 D-TG小鼠中肝脏的兼性祖细胞，卵圆细胞的活化，因为它们具有作为癌症干细胞的潜在作用。我们将再次利用3-连环蛋白抑制来检查针对该干细胞群体的治疗潜力。确定肝癌发展和癌症干细胞活化中的关键分子参与者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，是全球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，以及靶向这种原因的适用性将对肝癌治疗产生重大影响。