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:
- 金额:$ 15.53万
- 依托单位:
- 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:
- 关键词:AddressAnimal ModelBiological AssayBiological ModelsCancer EtiologyCarcinomaCell Cycle CheckpointCell ProliferationCessation of lifeCharacteristicsClinicalClinical DataData SetDevelopmentDiethylnitrosamineDiseaseGenesGeneticHepatocarcinogenesisHepatocyteHeterogeneityHumanIncidenceInvadedInvestigationKnowledgeLiverLiver diseasesLocationLymphomaMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of liverMeta-AnalysisMitoticMolecularMonitorMusMutationNeoplasmsOncogenicOutcomePLK1 genePathogenesisPatientsPlayPre-Clinical ModelPrimary carcinoma of the liver cellsPropertyProto-OncogenesResearchRoleTestingTherapeuticTransgenesTransgenic MiceTransgenic ModelTransgenic OrganismsTumor Biologycancer therapycancer typedruggable targetin vivoinsightmortalitymouse modelnovelsarcomasenescencetargeted treatmenttooltumortumorigenesis
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
肝细胞癌是人类最常见的恶性肿瘤之一
项目成果
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