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

• 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
• 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

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

肝细胞癌是人类最常见的恶性肿瘤之一。 和全球癌症相关死亡的主要原因，发病率和 。肝细胞癌的一个主要特征是其临床表现和 潜在的肿瘤生物学。因此，迫切需要了解分子 探讨该病的发病机制，并探讨治疗该病的新靶点和策略 肝细胞癌。哺乳动物Polo-like kinase1(Plk1)是一种关键的有丝分裂调节因子，参与了 各种癌症的发生和发展，包括肝癌，并已 随后被强调为抗癌治疗的一个有前途的靶点。我们生成了Plk1 Plk1表达全局升高的转基因小鼠，其在 与野生型小鼠相比，肿瘤发病率最高，其中肝癌位居第二 观察到主要的肿瘤。此外，我们对公开可获得的临床数据的荟萃分析 数据集显示Plk1在肝细胞癌中频繁上调，且显著相关 患者存活率较低。强有力的临床证据和惊人的异常表现 Plk1转基因小鼠的肝脏强烈提示Plk1在肝癌发病机制中的作用 发展，从而促使我们研究Plk1水平升高是否会驱动肝脏 致癌。在这项研究中，我们建议定义Plk1在肝细胞癌中的致癌作用 使用转基因小鼠模型进行的研究。中心假设是Plk1 在肝细胞癌中起重要的原癌基因作用。我们提出了以下具体目标：1) 产生肝脏特异的Plk1转基因小鼠；以及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，我们将用它来明确地剖析致癌功能 并确定Plk1是否是肝癌发生的驱动基因 致命的疾病。从这项研究中获得的知识不仅将增进我们对 肝细胞癌的发病机制也为肝细胞癌的治疗提供了重要的见解，我们的 肝脏特异的Plk1转基因模型将成为检测其机制的理想的临床前模型。 以PLK1为靶点的晚期和转移性肝癌的基础治疗方法。此外， 这种动物模型为探索某些动物的相互作用提供了一个重要的研究工具。 在肝细胞癌患者中观察到的基因改变。PLK1的S功能可能会超越 我们的肝脏特异性Plk1转基因小鼠模型也将揭示其 可能在其他肝病中起作用。 死亡率