Targeting beta-catenin in liver pathology: Novel Interactions, Novel Paradigms

靶向肝脏病理学中的 β-连环蛋白：新的相互作用，新的范式

• 批准号: 8690843
• 负责人: Satdarshan Singh Monga
• 金额: $ 32.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690843
• 关键词: Accounting; Address; Adherens Junction; Adverse effects; Affect; Anabolism; Antioxidants; Ascorbic Acid; Biological; Biological Assay; Biological Process; Biology; CTNNB1 gene; Cell Adhesion; Cell Proliferation; Cell-Cell Adhesion; Cyclic AMP-Dependent Protein Kinases; Death Rate; Development; Diethylnitrosamine; Down-Regulation; Equilibrium; Event; Exons; Exposure to; Felis catus; Generations; Grant; Growth; Hepatic; Hepatoblastoma; Hepatocarcinogenesis; Hepatocyte; Human; In Vitro; Incidence; Injury; Investigation; Knockout Mice; Lead; Liver; Liver Fibrosis; Malignant Neoplasms; Medicine; Metabolic syndrome; Metabolism; Molecular; Morphologic artifacts; Mus; Natural regeneration; Outcome; Oxidative Stress; PDGFRB gene; PTPN11 gene; Pathology; Pathway interactions; Patient Selection; Phosphorylation; Primary carcinoma of the liver cells; Primates; Process; Proteins; Regulation; Reporting; Research Proposals; Rodent; Role; Serine; Serine/Threonine Phosphorylation; Serum; Signal Pathway; Signal Transduction; Site; Somatic Mutation; Testing; Threonine; Up-Regulation; Ursidae Family; arm; ascorbate; base; beta catenin; cancer cell; cancer therapy; chemical carcinogen; dietary supplements; hepatoma cell; in vivo; liver injury; novel; prevent; public health relevance; research study; therapeutic target; therapy resistant; tumorigenesis

DESCRIPTION (provided by applicant): Wnt/¿-catenin signaling is pertinent in liver biology in regulating zonation, regeneration, development and metabolism. However aberrations in this pathway have been reported in hepatic fibrosis, hepatic injury, hepatoblastomas and hepatocellular cancer (HCC). Targeting ¿ -catenin in HCC is imminent. It is the 3rd fatal cancer worldwide and its incidence and associated death rates have steadily increased since the 1980s. Cellular & molecular basis of HCC is poorly understood. Wnt signaling has been deemed active in 17-40% of HCCs due to various reasons and around 20-40% of all HCCs harbor monoallelic somatic mutations in the exon-3 of the ¿-catenin gene (CTNNB1) that encodes for a non-serine/threonine phosphorylatable, stable and constitutively active protein, making it an attractive therapeutic target. We have made several important and some paradoxical observations over the last few years including identification of novel interactions and cross-regulations between ¿ -catenin and other molecules. These may have significant biological and translational implications mandating an in-depth analysis that may have widespread implications in not just HCC but other hepatic pathologies where ¿ -catenin targeting may be of essence such as hepatic fibrosis, injury and metabolic syndrome. The overarching hypothesis of the proposal is that therapeutic targeting of ¿ -catenin must take into account existing redundancies and crosstalk with specific signaling pathways, which need to be comprehensively elucidated. We will test these hypotheses in three distinct but thematically related aims. In aim 1, we will investigate the mechanism of oxidative stress dependent enhanced hepatocarcinogenesis in ¿ -catenin conditional knockout mice (Hep- ¿ -Cat KO) to address if enhanced HCC is a murine 'artifact' due to the role of - ¿ catenin in vitamin C biosynthesis in murine hepatocytes. We identified a novel role of ¿ -catenin signaling in vitamin C biosynthesis in the murine liver, whic is a known major antioxidant. Unlike humans and primates, rodents synthesize vitamin C in the hepatocytes and regular mouse chow is devoid of ascorbic acid. We hypothesize that increased HCC and oxidative stress in Hep- ¿ -Cat KO is due to compromised vitamin C biosynthesis and its normalization will alleviate HCC and demonstrate ¿ -catenin to be a global therapeutic target in HCC. In aim 2 we will investigate mechanism and biological implications of PDGFR¿ upregulation and activation after ¿-catenin inhibition in HCC cells. We hypothesize that PDGFR¿ upregulation along with the activation of its specific downstream signaling arm is an important mechanism that will allow growth of HCC after ¿-catenin inhibition and that understanding the role and regulation of this phenomena will bear significantly on efficacious HCC treatment. In aim 3, we will investigate the role and regulation of ?-catenin stabilization following inhibition of ¿-catenin expression in the liver. We hypothesize that ?-catenin stabilization during ¿-catenin inhibition in HCC will prevent any untoward effect related to disruption of cell-cell adhesion. All the proposed studies in the grant will utilize a balance of i vitro and in vivo set of experiments and the expected outcomes will be highly relevant and translational.

描述（由申请人提供）：Wnt/¿ -连环蛋白信号传导在肝脏生物学中与调节分区、再生、发育和代谢相关，然而，在肝纤维化、肝损伤、肝母细胞瘤和肝细胞癌 (HCC) 中已报道了该途径的异常。 HCC 中的连环蛋白已成为全球第三大致命癌症，自 20 世纪 80 年代以来，人们对 HCC 的细胞和分子基础知之甚少。由于各种原因，HCC 中约 20-40% 的 HCC 外显子 3 存在单等位体细胞突变。 -连环蛋白基因 (CTNNB1) 编码一种非丝氨酸/苏氨酸磷酸化、稳定且具有组成型活性的蛋白质，使其成为有吸引力的治疗靶标。在过去几年中，我们进行了一些重要且有些矛盾的观察，包括识别新的相互作用和之间的交叉监管-连环蛋白和其他分子。这些可能具有重要的生物学和翻译意义，需要进行深入的分析，不仅对 HCC 而且对其他肝脏病理学也有广泛的影响。 -连环蛋白靶向可能对肝纤维化、损伤和代谢综合征等至关重要。该提案的首要假设是 ¿ 的治疗靶向。 -连环蛋白必须考虑到现有的冗余和与特定信号通路的串扰，这需要全面阐明。在目标 1 中，我们将研究氧化应激依赖性增强肝癌发生的机制。在 -连环蛋白条件性基因敲除小鼠 (Hep-¿ -Cat KO)，以解决由于 - ¿ 的作用而导致的增强型 HCC 是否是小鼠“人为因素”的问题连环蛋白在小鼠肝细胞维生素 C 生物合成中的新作用鼠类肝脏中维生素 C 生物合成中的连环蛋白信号是一种已知的主要抗氧化剂，与人类和灵长类动物不同，啮齿类动物在肝细胞中合成维生素 C，而普通小鼠食物中缺乏抗坏血酸。 Hep-¿ -Cat KO 是由于维生素 C 生物合成受损，其正常化将减轻 HCC 并证明 ¿ -连环蛋白成为 HCC 的全球治疗靶标 在目标 2 中，我们将研究 PDGFR 的机制和生物学意义。 ¿ 后上调和激活-HCC 细胞中的连环蛋白抑制。上调及其特定下游信号臂的激活是一个重要机制，将允许 HCC 生长后 ¿ β-连环蛋白抑制以及了解这种现象的作用和调节将对有效的 HCC 治疗产生重大影响。在目标 3 中，我们将研究抑制 ¿ 后 β-连环蛋白稳定的作用和调节。 β-连环蛋白在肝脏中的表达。 HCC 中的连环蛋白抑制将防止与细胞间粘附破坏相关的任何高度不良影响。该资助中的所有拟议研究将利用体外和体内实验组的平衡，预期结果将是相关的和转化的。