PEA15 IN DEVELOPMENT OF LIVER CANCER AND ITS THERAPEUTIC IMPLICATION

摘要和摘要 肝癌是世界上最常见的癌症之一，每年估计有60万人死亡。 在过去的25年里，美国的肝癌发病率有所增加，而 预计在未来10到20年内，肝细胞癌的死亡率将翻一番。发病率的增加 肝细胞癌的高死亡率更是雪上加霜。年肝细胞癌患者总的五年生存率 美国约为16%，使肝癌成为仅次于胰腺癌的最致命的癌症类型。 尽管肝癌很重要，但与其他主要致命性癌症相比，它的研究还不够充分，因此，我们的 与发病、进展和临床相关的遗传或表观遗传改变的知识 肝细胞癌的治疗结果仍不完整。此外，只有有限的治疗方案可供选择。 不到三分之一的肝癌患者有资格接受潜在的根治疗法，如 切除、移植或经皮消融。具有抗血管生成作用的多激酶抑制剂索拉非尼 和抗增殖作用，已被证明可提高这些患者的存活率，并已成为 晚期肝细胞癌的护理标准。然而，不幸的是，索拉非尼治疗的好处似乎是 边际延长只有2.8个月的总存活率和只有2%的令人沮丧的应答率，突出显示 迫切需要新的靶向药物或寻找新的方法来克服对索拉非尼的耐药性。 通过分析人类肝癌的蛋白质组和基因组数据，我们发现了三个分子和 临床上不同的肝细胞癌蛋白质组亚型。蛋白质组数据与基因组数据的整合分析 进一步证明PEA15在肝细胞癌基因组中高度扩增，其扩增和表达 与预后不良显著相关。它的扩增不限于在膀胱癌中扩增 癌症、肺癌和乳腺癌。我们证明了PEA15在绝大多数细胞中上调 它对肝癌细胞的增殖和存活是必不可少的。我们进一步证明了 PEA15促进癌症的侵袭。我们的研究还表明，高表达PEA15的肝癌细胞 对血管生成负责。 在拟议的研究中，我们的目标是(1)确定PEA15在肝癌发生发展中的作用。(二)确定 PEA15在血管生成中的作用(3)确定PEA15是否是治疗肺癌的良好靶点 肝细胞癌。如果成功，这将为开发新的治疗方法开辟新的机会。 肝细胞癌患者预后不良。此外，从这项研究中获得的知识可以用于其他 PEA15高度扩增的癌症类型(即膀胱癌、肺癌和乳腺癌) 与生存有关。

Summary and Abstract HCC is one of the most common cancers worldwide, accounting for an estimated 600,000 deaths annually. The incidence of HCC has increased in the United States over the past 25 years and the incidence of and mortality rate for HCC are expected to double over the next 10 to 20 years. The increased incidence rate is exacerbated by high mortality rate of HCC. The overall five-year survival rates of patients with HCC in the United States are around 16%, making HCC the most lethal cancer type after pancreatic cancer. Despite its importance, HCC is understudied compared to other major lethal cancers, and hence, our knowledge of the genetic or epigenetic alterations associated with the initiation, progression, and clinical outcomes of HCC is still fragmentary. Furthermore, there is only a limited arsenal of treatment options for HCC as less than one-third of patients with HCC are eligible for potentially curative treatments such as resection, transplantation, or percutaneous ablation. Sorafenib, a multi-kinase inhibitor with antiangiogenic and anti-proliferative effects, has been shown to improve survival in these patients, and has become the standard of care in advanced HCC. However, unfortunately, benefit of sorafenib treatment appears to be marginal extending only 2.8 months of overall survival and a dismal response rate of only 2%, highlighting the urgent need for new targeted agents or finding new ways to overcome resistant to sorafenib. By analyzing proteomic and genomic data from human HCC, we uncovered three molecularly and clinically distinct proteomic subtype of HCC. Analysis with integrated proteomic data with genomic data further showed that PEA15 is highly amplified in HCC genome and its amplification and expression are significantly associated with poor prognosis. Its amplification is not limited to HCC as amplified in bladder cancer, lung cancer, and breast cancer. We demonstrated that PEA15 is up-regulated in vast majority of HCC cell lines and it is essential for proliferation and survival of HCC cells. We further demonstrated that PEA15 promotes invasion of cancer. Our study also showed HCC cells with high PEA15 expression is accountable for angiogenesis. In proposed study, we aim to (1) determine roles of PEA15 in HCC developments. (2) determine roles of PEA15 in angiogenesis. (3) determine if PEA15 is good therapeutic targets for treatment of HCC. If successful, this will open up new opportunity for development of novel therapeutic approaches for poor prognostic patients with HCC. Furthermore, knowledge obtained from this study can be used in other cancer type (i.e. bladder cancer, lung cancer, and breast cancer) in which PEA15 is highly amplified and associated with survival.