Inducible systems for studying liver tumor mainenance in vivo

用于研究肝脏肿瘤体内维持的诱导系统

• 批准号: 9457376
• 负责人: Xin Chen
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9457376
• 关键词: Ablation; Address; BAY 54-9085; Cancer Etiology; Cessation of life; Clinical Trials; Complex; Critical Pathways; Data; Development; Disease; EIF4EBP1 gene; Event; FRAP1 gene; Gene Expression; Genes; Genetic; Genetic Engineering; Goals; Hepatocarcinogenesis; Injections; Lead; Life; Liver; Liver neoplasms; MAP Kinase Gene; MYC gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Molecular Genetics; Mus; Oncogenes; Pathogenesis; Pathway interactions; Patients; Primary carcinoma of the liver cells; Raptors; Research; Research Project Grants; Role; SDZ RAD; Signal Pathway; Signal Transduction; Sirolimus; Sleeping Beauty; Solid; Study models; System; Technology; Testing; Transfection; beta catenin; c-myc Genes; effective therapy; experimental study; flexibility; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; targeted treatment; tumor; tumor growth; tumor initiation; tumor progression

Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. However, molecular genetics underlying HCC development remain to be poorly understood. Treatment options for HCC are very limited and in general ineffective. There is only a single option for treatment of advanced HCC (Sorafenib) which prolongs life by an average of just three months! Consequently, there is a pressing unmet need for new insights on HCC that will lead to new therapies. The growing understanding of molecular pathogenesis of HCC, on the other hand, does open the door for novel strategy of targeted therapy. Hydrodynamic transfection combines hydrodynamic injection together with sleeping beauty mediated somatic integration for long term gene expression. Because of its flexibility and high efficiency, it has now becoming increasingly popular to be used to generate murine models for studying hepatocarcinogenesis. However, so far few inducible systems have been established for this technology. Amplification and overexpression of c-Myc oncogene is one of the most frequently observed genetic events during HCC pathogenesis; and c-Myc is considered to be an important driver oncogene for HCC. Indeed overexpression of c-Myc in mouse liver promotes the formation of poorly differentiated HCC. Recently, we discovered that ablation of Raptor, the unique component of mTORC1, significantly suppressed c-Myc driven HCC development in vivo. However, it is not clear whether mTORC1 is required for c-Myc HCC maintenance and whether inhibition of mTORC1 leads to HCC regression. In this application, we hypothesize that mTORC1 is required for c-Myc maintenance; and deleting Raptor after tumor formation will lead to tumor regression. In this R03 small application, we will establish an efficient inducible Cre system for hydrodynamic transfection (Aim 1). We will then apply the technology to delete Raptor in c-Myc induced HCC tumors in vivo with the goal to study whether mTORC1 complex is required for maintaining c-Myc HCC (Aim 2). Altogether, this is a self-contained research projects which fits well with the description and scope of a R03 small research project. It assists to develop a powerful research technology which can be used to characterize the requirement of a gene or pathway for HCC maintenance. The results from such studies are critical for establishing the gene or pathway for the treatment of HCC.

抽象的 肝细胞癌 (HCC) 是第五大常见癌症，也是癌症死亡的第三大原因 全世界。然而，HCC 发展的分子遗传学仍然知之甚少。 HCC 的治疗选择非常有限，而且通常无效。只有一个选项 治疗晚期肝癌（索拉非尼），平均仅延长三个月生命！最后， 对 HCC 新见解的迫切需求尚未得到满足，这将带来新的治疗方法。不断成长的 另一方面，对 HCC 分子发病机制的了解确实为新策略打开了大门 靶向治疗。水动力转染将水动力注射与睡美结合起来 介导体细胞整合以实现长期基因表达。由于其灵活性和高效率， 现在越来越流行用于生成研究肝癌发生的小鼠模型。 然而，迄今为止，针对该技术建立的诱导系统还很少。放大和 c-Myc 癌基因的过度表达是 HCC 期间最常见的遗传事件之一 发病;而c-Myc被认为是HCC的重要驱动癌基因。确实过度表达 小鼠肝脏中的 c-Myc 促进低分化 HCC 的形成。最近，我们发现 mTORC1 的独特成分 Raptor 的消融可显着抑制 c-Myc 驱动的 HCC 体内发育。然而，尚不清楚 mTORC1 是否是 c-Myc HCC 维持所必需的，并且 抑制 mTORC1 是否会导致 HCC 消退。在此应用中，我们假设 mTORC1 是 c-Myc 维护所需；肿瘤形成后删除Raptor将导致肿瘤消退。在这个 R03小应用，我们将建立一个高效的诱导型Cre系统用于水动力转染（目标1）。 然后，我们将应用该技术删除 c-Myc 诱导的体内 HCC 肿瘤中的 Raptor，目的是研究 维持 c-Myc HCC 是否需要 mTORC1 复合物（目标 2）。总而言之，这是一个 独立的 与 R03 小型研究项目的描述和范围非常吻合的研究项目。它有助于 开发一种强大的研究技术，可用于表征基因或基因的需求 HCC 维持途径。此类研究的结果对于建立基因或 HCC 的治疗途径。