Intra- and inter-cellular signals that drive hepato-oncogenesis

驱动肝肿瘤发生的细胞内和细胞间信号

基本信息

批准号：
10557925
负责人：
Gen-Sheng Feng
金额：
$ 41.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557925
关键词：
Ablation Animal Model Automobile Driving BAY 54-9085 Cells Cessation of life Chemicals Clinical Complement Data Diethylnitrosamine Disease Environment Environmental Risk Factor Epidermal Growth Factor Receptor Excision Goals Hepatic Hepatocarcinogenesis Hepatocyte Human Immunotherapy Liver Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Modeling Molecular Mus NF-kappa B Oncogenes Oncogenic Oncoproteins Oxidative Stress PIK3CA gene Paper Pathogenicity Pathway interactions Patients Pharmacologic Substance Pharmacy (field)Phenotype Play Primary carcinoma of the liver cells Process Proteins Publishing Research Role Sampling Signal Pathway Signal Transduction Sister TP53 gene Testing Therapeutic Transfection Tumor Promotion Tumor Suppressor Proteins beta catenin cancer type chemical carcinogen design experimental study genetic analysis interdisciplinary approach kinase inhibitor liver cancer model liver cancer patient liver inflammation liver injury mouse model novel novel therapeutic intervention single-cell RNA sequencing theories therapeutically effective tumor tumorigenesis tumorigenic

Ablation Animal Model Automobile Driving BAY 54-9085 Cells Cessation of life Chemicals Clinical Complement Data Diethylnitrosamine Disease Environment Environmental Risk Factor Epidermal Growth Factor Receptor Excision Goals Hepatic Hepatocarcinogenesis Hepatocyte Human Immunotherapy Liver Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Modeling Molecular Mus NF-kappa B Oncogenes Oncogenic Oncoproteins Oxidative Stress PIK3CA gene Paper Pathogenicity Pathway interactions Patients Pharmacologic Substance Pharmacy (field)Phenotype Play Primary carcinoma of the liver cells Process Proteins Publishing Research Role Sampling Signal Pathway Signal Transduction Sister TP53 gene Testing Therapeutic Transfection Tumor Promotion Tumor Suppressor Proteins beta catenin cancer type chemical carcinogen design experimental study genetic analysis interdisciplinary approach kinase inhibitor liver cancer model liver cancer patient liver inflammation liver injury mouse model novel novel therapeutic intervention single-cell RNA sequencing theories therapeutically effective tumor tumorigenesis tumorigenic

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项目摘要

Liver cancer, mainly hepatocellular carcinoma (HCC), has become a most deadly malignant disease worldwide. So far, pharmaceutic inhibition of major oncogenic pathways has achieved little therapeutic benefit to liver cancer patients. We believe this is due to under- appreciation of the complexity in mechanisms of hepato-oncogenesis. In recent experiments, we and others have identified paradoxically anti-oncogenic effects of classical oncogenic molecules, such as c-Met, EGFR, β-catenin, Ikkβ, Jnk, and Shp2, in the liver. Ablating these molecules in hepatocytes enhanced HCC induced by chemical carcinogen DEN. To test a theory that loss of the oncogenic molecules generates an oncogenic microenvironment that promotes DEN-induced HCC, we have established another mouse HCC model, by transfection of oncogenic β-catenin (CAT), c-Met (MET) and PIK3CA (PIK), oncoproteins frequently detected in human HCCs. As expected, MET/CAT-driven HCC was aggravated in β-catenin-deficient liver, due to tumor-promoting factors induced by β-catenin removal. In contrast, Shp2 deletion dramatically suppressed HCC driven by MET/CAT or MET/PIK, despite a similar pro-tumorigenic environment in Shp2-deficient liver. Based on these novel unanticipated data, we propose a new hypothesis that although removal of Shp2 or β-catenin generates cell-extrinsic tumorigenic factors in the hepatic environment, the endogenous Shp2 is indispensable for oncogenic signaling in hepatocytes. To test this hypothesis, we propose three specific aims on this project. Aim 1 is to determine the cell-intrinsic role of Shp2 in hepato-oncogenic signaling. Aim 2 is to determine the cell-autonomous effect of β-catenin in liver tumorigenesis. Aim 3 is to search and identify cell-extrinsic factors induced by loss of the oncoproteins in hepatocytes. The results are expected to be instrumental for design of novel therapeutic strategies for liver cancer by inhibiting both cell-intrinsic oncogenic signals and the secondary environmental factors.

肝癌，主要是肝细胞癌（HCC），已成为最致命的全球恶性疾病。到目前为止，药物对主要致癌途径的抑制作用它几乎没有对肝癌患者获得的治疗益处。我们认为这是由于不足欣赏肝结合发生机制的复杂性。在最近的实验中，我们和其他人已经确定了经典致癌性的矛盾的抗疾病作用肝脏中的分子，例如C-MET，EGFR，β-catenin，Ikkβ，JNK和SHP2。减轻这些化学致癌物诱导的肝细胞中的分子增强了HCC。测试理论认为，致癌分子的丧失会产生一种致癌的微环境，即促进DEN引起的HCC，我们建立了另一个鼠标HCC模型，致癌β-catenin（CAT），C-MET（MET）和PIK3CA（PIK），癌蛋白的转染经常在人类HCC中检测到。不出所料，MET/CAT驱动的HCC聚集在由于去除β-catenin诱导的肿瘤促进因子，β-catenin缺乏肝脏。在对比，SHP2删除大大抑制了由MET/CAT或MET/PIK驱动的HCC，尽管在SHP2缺陷肝脏中也有类似的促肿瘤环境。基于这些小说意外数据，我们提出了一个新的假设，即尽管去除SHP2或β-catenin 在肝脏环境中产生细胞 - 肢体肿瘤因子，内源性SHP2 对于肝细胞中的致癌信号传导是必不可少的。为了检验这一假设，我们提出了该项目的三个具体目标。 AIM 1是确定SHP2的细胞中性作用肝癌信号传导。目标2是确定β-catenin在肝肿瘤发生。 AIM 3是搜索和识别因丢失而引起的细胞超支因子肝细胞中的癌蛋白。预计结果将有助于新颖的设计肝癌的治疗策略是通过抑制细胞中性致癌信号和次要环境因素。