Define the oncogenic role of Plk1 during hepatocellular carcinoma development using a genetically modified mouse model

使用转基因小鼠模型定义 Plk1 在肝细胞癌发展过程中的致癌作用

基本信息

批准号：
10729603
负责人：
ZHENG FU
金额：
$ 15.53万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729603
关键词：
Address Animal Model Biological Assay Biological Models Cancer Etiology Carcinoma Cell Cycle Checkpoint Cell Proliferation Cessation of life Characteristics Clinical Clinical Data Data Set Development Diethylnitrosamine Disease Genes Genetic Hepatocarcinogenesis Hepatocyte Heterogeneity Human Incidence Invaded Investigation Knowledge Liver Liver diseases Location Lymphoma Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Meta-Analysis Mitotic Molecular Monitor Mus Mutation Neoplasms Oncogenic Outcome PLK1 gene Pathogenesis Patients Play Pre-Clinical Model Primary carcinoma of the liver cells Property Proto-Oncogenes Research Role Testing Therapeutic Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Tumor Biology cancer therapy cancer type druggable target in vivo insight mortality mouse model novel sarcoma senescence targeted treatment tool tumor tumorigenesis

项目摘要

Hepatocellular carcinoma (HCC) represents one of the most common malignancies in humans and the leading cause of cancer-related death worldwide, with a steadily increasing incidence and . A major hallmark of HCC is its high heterogeneity in clinical presentation and underlying tumor biology. Therefore, there is an urgent need to understand the molecular pathogenesis of the disease, and to explore novel targets and strategies for the management of HCC. Mammalian polo-like kinase 1 (Plk1) is a key mitotic regulator that has been implicated in the initiation and progression of various types of cancer, including liver cancers, and has subsequently been highlighted as a promising target for anticancer therapy. We generated Plk1 transgenic mice with globally elevated expression of Plk1, which showed marked increases in tumor incidence, when compared to wild-type littermates, with HCC being the second most predominant neoplasm observed. Furthermore, our meta-analysis of the publicly available clinical datasets demonstrates that Plk1 is frequently upregulated in HCC and is significantly correlated with poorer patient survival. The strong clinical evidence and the striking abnormality present in the livers of Plk1 transgenic mice strongly suggests a role of Plk1 in the pathogenesis of HCC development, and thereby prompted us to investigate whether elevated levels of Plk1 drives liver carcinogenesis. In this study, we propose to define the oncogenic role of Plk1 during HCC development using a genetically modified mouse model. The central hypothesis is that Plk1 functions as a prominent proto-oncogene in HCC. We propose the following specific aims: 1) Generate liver-specific Plk1 transgenic mice; and 2) Determine hepatocarcinogenesis in liver- specific Plk1 transgenic mice. This study will allow us to establish the first liver-specific Plk1 transgenic murine model, with which we will use to unambiguously dissect the oncogenic function of Plk1 during hepatocarcinognesis and determine whether Plk1 is a driver gene of this invariably fatal disease. The knowledge gained from this study will not only enhance our understanding of the pathogenesis of HCC also provide important insights into the management of HCC, and our liver-specific Plk1 transgenic model will serve as the ideal pre-clinical model to test mechanism- based therapeutic approaches that target PLK1 in advanced and metastatic HCC. Furthermore, this animal model provides an important research tool for exploring interactions of some of the genetic alterations observed in HCC patients. Plk1’s function may go beyond hepatocarcinogenesis; our liver-specific Plk1 transgenic mouse model will also shed light on its possible role in other liver diseases. mortality rate

肝细胞癌 (HCC) 是人类最常见的恶性肿瘤之一是全球癌症相关死亡的主要原因，其发病率和发病率稳步上升 HCC 的一个主要特点是其临床表现的高度异质性和因此，迫切需要了解肿瘤的分子生物学。疾病的发病机制，并探索新的治疗目标和策略哺乳动物 Polo 样激酶 1 (Plk1) 是一种关键的有丝分裂调节因子，与 HCC 相关。包括肝癌在内的各种癌症的发生和进展随后，我们生成了 Plk1，作为抗癌治疗的一个有前景的靶点。 Plk1 表达全面升高的转基因小鼠，显示出与野生型同窝小鼠相比，肿瘤发生率，HCC 是第二高的此外，我们对公开的临床数据进行了荟萃分析。数据集表明 Plk1 在 HCC 中频繁上调，并且显着相关强有力的临床证据和显着的异常存在于患者的生存中。 Plk1 转基因小鼠的肝脏强烈表明 Plk1 在 HCC 发病机制中的作用发育，从而我们研究肝脏驱动水平升高是否会促使在这项研究中，我们建议定义 Plk1 在 HCC 过程中的致癌作用。使用转基因小鼠模型进行开发的核心假设是 Plk1。作为 HCC 中重要的原癌基因，我们提出以下具体目标：1) 生成肝脏特异性 Plk1 转基因小鼠；2) 确定肝脏中的肝癌发生特异性 Plk1 转基因小鼠这项研究将使我们能够建立第一个肝脏特异性 Plk1。转基因小鼠模型，我们将用它来明确剖析致癌功能肝癌发生过程中 Plk1 的变化并确定 Plk1 是否是肝癌发生的驱动基因从这项研究中获得的知识不仅会增强我们对致命疾病的理解。 HCC 的发病机制也为 HCC 的治疗提供了重要的见解，我们的研究也为 HCC 的治疗提供了重要的见解。肝脏特异性 Plk1 转基因模型将作为测试机制的理想临床前模型 - 基于 PLK1 的晚期和转移性 HCC 治疗方法。该动物模型为探索某些相互作用提供了重要的研究工具在 HCC 患者中观察到的基因改变可能超出了 Plk1 的功能范围。我们的肝脏特异性 Plk1 转基因小鼠模型也将揭示其肝癌发生过程在其他肝脏疾病中可能发挥作用。死亡率