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