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Initiation, persistence, and progression of hepatocellular carcinoma

肝细胞癌的发生、持续和进展

基本信息

批准号：
8069940
负责人：
EDWARD E SCHMIDT
金额：
$ 12.03万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-07 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069940
关键词：
Adolescent Affect Age Age-Months Alcoholic Liver Cirrhosis Alleles Animal Model Animals Antineoplastic Agents Apoptosis Applications Grants Birth Cancer Model Cancerous Cells Cessation of life Chimera organism Chronic Cirrhosis Complex Control Groups DNA Development Diagnosis Diethylnitrosamine Disease Drug Combinations Drug Delivery Systems Drug Kinetics Early Diagnosis Excision Fetal Liver Fostering Frequencies Future Genes Genetic Genomics Genotype Goals Growth Harvest Health Hepatitis B Hepatitis C Hepatocyte Human In Situ Incidence Individual Inflammatory Intention Investigation Lead Liver Liver diseases Liver neoplasms Longevity Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Measures Metabolic Metabolism Metals Minority Modeling Mus National Cancer Institute Neoplasm Metastasis Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Physiological Play Primary carcinoma of the liver cells Process Prognostic Marker Prophylactic treatment Protein p53 RNA Recurrence Refractory Reverse Transcriptase Polymerase Chain Reaction Role Sampling Solutions Staging Survival Rate System Time Toxic effect Transplantation Tumor Markers Waiting Lists base cancer cell cancer initiation cancer therapy carcinogenesis cell type chemotherapy combinatorial cost drug candidate drug metabolism efficacy testing improved in utero juvenile animal liver metabolism liver transplantation men novel novel therapeutics outcome forecast prevent pup research study response thioredoxin reductase thioredoxin reductase 1 tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the 3rd most lethal cancer worldwide. Liver transplant remains the only therapy with a favorable prognosis, and even in these cases, 5-year survival rates are low and recurrence is common 1. Moreover, donor livers are in short supply, and the cost and technical difficulty of transplantation puts therapy out of reach of all by a small minority of people stricken with the disease. Clearly there is a need for pharmaceutical-based therapies for this disease, even if just to extend longevity after transplant. However, the complexities of liver metabolism have kept this goal out of reach. Cytoplasmic thioredoxin reductase (Txnrd1) plays a major role in liver metabolism. Many anti-cancer drugs or drug-candidates, as well as some compounds thought to be active in prophylaxis against cancer initiation, either affect Txnrd1 activity or are substrates for metabolism by Txnrd1 5,6. This suggests that Txnrd1 plays crucial roles in cancer initiation, persistence, and progression. However, prior to now, no studies have been performed in systems having complete and specific genetic disruption of Txnrd1. Therefore, it is unclear what role Txnrd1 plays in responses to these compounds, and what roles undefined 'other targets' might play. We have developed the first animal model with Txnrd1-deficient hepatocytes 3. In the proposed study, we will develop the first animal model with Txnrd1-deficient HCC and to use this model to study initiation, persistence, and progression of HCC in cells that either have or lack Txnrd1. To do this, we have put forth two Specific Aims. First, we will determine whether Txnrd1-deficient hepatocytes are either more susceptible or more refractory than normal hepatocytes to initiation of HCC. Second, we will determine whether Txnrd1 activity is necessary, advantageous, or antagonistic for persistence and progression of HCC cells in situ. This two-year Developmental R21 project is proposed with the intention of establishing and publicly disseminating a novel and powerful animal model for studying HCC, and to provide important understanding of the roles of Txnrd1 in cancer initiation and persistence/progression.

描述（由申请人提供）：肝细胞癌（HCC）是全球第三大致死性癌症。肝移植仍然是唯一具有良好预后的治疗方法，即使在这些病例中，5年生存率也很低，复发也很常见。此外，供体肝脏供应短缺，移植的成本和技术难度使少数患有这种疾病的人无法获得治疗。显然，需要针对这种疾病的药物治疗，即使只是为了延长移植后的寿命。然而，肝脏代谢的复杂性使这一目标遥不可及。细胞质硫氧还蛋白还原酶（Txnrd 1）在肝脏代谢中起着重要作用。许多抗癌药物或候选药物，以及一些化合物被认为是积极的预防癌症的开始，要么影响Txnrd 1活性或代谢的Txnrd 1底物5，6。这表明Txnrd 1在癌症的发生、持续和进展中起着至关重要的作用。然而，在此之前，尚未在具有Txnrd 1的完全和特异性遗传破坏的系统中进行研究。因此，目前还不清楚Txnrd 1在对这些化合物的反应中起什么作用，以及未定义的“其他靶点”可能起什么作用。我们已经开发了第一个Txnrd 1缺陷肝细胞的动物模型3。在拟议的研究中，我们将开发第一个Txnrd 1缺陷型HCC动物模型，并使用该模型研究具有或缺乏Txnrd 1的细胞中HCC的发生、持续和进展。为此，我们提出了两个具体目标。首先，我们将确定Txnrd 1缺陷肝细胞是否比正常肝细胞更易发生或更难发生HCC。其次，我们将确定Txnrd 1活性是否是必要的，有利的，或拮抗性肝癌细胞原位的持久性和进展。这个为期两年的发展R21项目的目的是建立和公开传播一个新的和强大的动物模型，用于研究肝癌，并提供重要的理解Txnrd 1在癌症的发生和持续/进展的作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver.

DOI：
10.1038/ncomms7479
发表时间：
2015-03-20
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Eriksson, Sofi;Prigge, Justin R.;Talago, Emily A.;Arner, Elias S. J.;Schmidt, Edward E.
通讯作者：
Schmidt, Edward E.

Interplay between cytosolic disulfide reductase systems and the Nrf2/Keap1 pathway.

DOI：
10.1042/bst20150021
发表时间：
2015-08
期刊：
Biochemical Society transactions
影响因子：
3.9
作者：
Schmidt EE
通讯作者：
Schmidt EE

Contributions of new hepatocyte lineages to liver growth, maintenance, and regeneration in mice.

新的肝细胞谱系对小鼠肝脏生长，维持和再生的贡献。

DOI：
10.1002/hep.24398
发表时间：
2011-08
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Iverson, Sonya V.;Comstock, Kristin M.;Kundert, Jean A.;Schmidt, Edward E.
通讯作者：
Schmidt, Edward E.

A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.

DOI：
10.1016/j.freeradbiomed.2013.05.028
发表时间：
2013-10
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Iverson SV;Eriksson S;Xu J;Prigge JR;Talago EA;Meade TA;Meade ES;Capecchi MR;Arnér ES;Schmidt EE
通讯作者：
Schmidt EE

Hepatocyte DNA replication in growing liver requires either glutathione or a single allele of txnrd1.

DOI：
10.1016/j.freeradbiomed.2011.11.025
发表时间：
2012-02-15
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Prigge, Justin R.;Eriksson, Soil;Iverson, Sonya V.;Meade, Tesia A.;Capecchi, Mario R.;Arner, Elias S. J.;Schmidt, Edward E.
通讯作者：
Schmidt, Edward E.