Initiation, persistence, and progression of hepatocellular carcinoma

描述（由申请人提供）：肝细胞癌（HCC）是全球第三大致命癌症。肝移植仍然是唯一预后良好的治疗方法，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得一小部分患有这种疾病的人无法接受治疗。很明显，这种疾病需要基于药物的治疗，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无法实现。胞质硫氧还蛋白还原酶（Txnrd1）在肝脏代谢中起重要作用。许多抗癌药物或候选药物，以及一些被认为对预防癌症起始有活性的化合物，要么影响Txnrd1的活性，要么是Txnrd1代谢的底物5,6。这表明Txnrd1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，还没有在Txnrd1完全和特异性遗传破坏的系统中进行过研究。因此，目前尚不清楚Txnrd1在对这些化合物的反应中起什么作用，以及未定义的“其他靶标”可能起什么作用。我们已经开发了第一个具有txnrd1缺陷肝细胞的动物模型。在本研究中，我们将建立第一个Txnrd1缺乏的HCC动物模型，并使用该模型研究具有或缺乏Txnrd1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txnrd1缺陷肝细胞是否比正常肝细胞更容易或更难发生HCC。其次，我们将确定Txnrd1活性对于原位HCC细胞的持续和进展是必要的、有利的还是拮抗的。这项为期两年的Developmental R21项目旨在建立并公开传播一种新的、强大的研究HCC的动物模型，并为Txnrd1在癌症发生和持续/进展中的作用提供重要的理解。

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.