The Impact of Arf1 on Hypoxia Signaling and Oral Cancer

项目总结 口腔鳞状细胞癌(OSCC)仍然是一个具有挑战性的临床问题，因为 当地和远程失败率居高不下。低氧在口腔鳞状细胞癌中普遍存在，通常 为最具侵袭性和转移性的肿瘤提供了强大的选择压力， 强调需要更好地了解分子机制和调节器 负责低氧条件下转移潜能的获取。我们现在有 数据表明，ADP-核糖化因子1(Arf1)，一种缺氧反应运输 蛋白质是低氧诱导口腔鳞状细胞癌侵袭和转移所必需的，也是足够的。这个 Arf1异常过表达和过度激活导致肿瘤侵袭潜能增加 低氧，增加了通过靶向Arf1来开发新方案的可能性，以便最终 提高口腔鳞癌治愈率。我们的首要目标是提高患者的存活率 通过揭示低氧和低氧下Arf1功能障碍的功能后果来实现口腔鳞癌 了解潜在的机制。这项提案有两个目的，以测试我们的 假设。目标1是剖析在转录和表观遗传方面的协同调控。 低氧诱导Arf1表达上调。目的2是为了说明分子机制和 低氧诱导Arf1过度激活的功能后果。这些初步研究将 为更全面地调查监管和作用提供了坚实的理由 低氧口腔鳞癌中的Arf1，将寻求未来R01机制的支持。总的来说，我们的 研究将通过探索Arf1 AS从机制上深入了解缺氧诱导的口腔鳞状细胞癌转移 一种新的缺氧肿瘤药物靶点，为Arf1靶向抗癌奠定基础 治疗方式。这一项目将直接影响《预言家》的未来发展 口腔鳞状细胞癌，尤其是低氧肿瘤的发病因素及治疗策略 微环境。

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) remains a challenging clinical problem because of the persisting high rate of local and distant failure. Hypoxia is prevalent in OSCC and often provides a strong selective pressure for the most aggressive and metastatic tumors, which emphasize the need for better understanding of molecular mechanisms and regulators responsible for the acquisition of metastatic potential under hypoxic conditions. We now have data demonstrating that ADP-ribosylation factor 1 (Arf1), a hypoxia-responsive trafficking protein, is required and sufficient to hypoxia-induced OSCC invasion and metastasis. The aberrant overexpression and hyperactivation of Arf1 leads to increased invasion potential upon hypoxia, raising the possibility to develop novel regimens by targeting Arf1 in order to eventually increase cure rate in OSCC. Our overarching goal is to improve the survival of patients with OSCC by revealing the functional consequences of Arf1 dysfunction under hypoxia and understanding the underlying mechanisms. There are two aims in the proposal to test our hypothesis. Aim 1 is to dissect the cooperatively transcriptional and epigenetic regulation in hypoxia-induced Arf1 upregulation. Aim 2 is to Illustrate the molecular mechanism and the functional consequences of hypoxia-induced Arf1 hyperactivation. These pilot studies will provide a solid rationale for a more comprehensive investigation into the regulation and role of Arf1 in hypoxic OSCC for which future R01 mechanism support will be sought. Overall, our studies will gain mechanistic insight into hypoxia-induced OSCC metastasis by exploring Arf1 as a novel druggable target for hypoxic tumors, and build a foundation for Arf1-targeted anticancer therapeutic modality. This project would directly impact the future development of prognostic variables and treatment strategies for OSCC, especially for those tumors in hypoxic microenvironment.