Role of EZH2 in Invasion and Migration in the Oral Mucosa

描述(申请人提供)：了解促进头颈癌(SCCHN)侵袭和扩散的机制将为治疗这种疾病提供新的基于机制的策略。SCCHN患者往往对治疗产生抵抗力，导致肿瘤复发。因此，几乎一半的SCCHN患者在确诊后五年内死亡。尽管前景黯淡，但40多年来一直没有新的治疗方法，这突显了新治疗策略的必要性。了解调节头颈癌的分子机制是有效治疗的关键。肿瘤起始细胞或干细胞，以及侵袭性细胞重新填充肿瘤，并在 “成功”治疗。由于侵袭、复发和扩散所需的细胞可塑性主要受表观遗传调控，因此针对表观遗传机制的治疗策略是重要的。这项拟议的研究集中于一种主要的表观遗传调控机制，该机制整合了侵袭性和干性通过上皮向间充质转化(EMT)介导的治疗耐药。中心假说是，EZH2通过诱导Rap1/EMT介导的侵袭和干化来促进SCCHN的进展和复发；这一关键作用使EZH2成为一个很好的治疗靶点。我们将通过追求以下目标来验证我们的假设：1)研究EZH2促进SCCHN侵袭的机制；2)确定EZH2诱导治疗耐药的机制；以及3)评估EZH2在人体组织中表达的临床相关性。我们将使用细胞系、2D和新颖的3D体外模型、新开发的人体SCCHN体内模型和人体组织来实现这一应用的目标。建议的研究将确定在SCCHN中Rap1整合表观遗传重新编程和EMT介导的侵袭、茎和治疗抗性的新机制。因此，我们的发现将有助于设计合理的治疗SCCHN的策略。

DESCRIPTION (provided by applicant): Understanding the mechanism that promotes invasion and spread of head and neck cancer (SCCHN) will provide novel mechanism-based strategies to treat this disease. Patients with SCCHN often develop resistance to treatment, which leads to tumor recurrence. Consequently, almost half of SCCHN patients die within five years of diagnosis. Despite this dismal outlook, there have been no novel treatments in over forty years, underscoring the need for new treatment strategies. Understanding the molecular mechanisms regulating head and neck cancers is essential for effective treatment. Tumor-initiating or stem cells, and invasive cells repopulate the tumor and spread to distant sites after "successful" treatment. Since cellular plasticity required for invasion, recurrence and spread is primarily regulated epigenetically, treatment strategies that target the epigenetic mechanism are important. The proposed study focuses on a major epigenetic regulatory mechanism that integrates invasion, and stemness-mediated treatment resistance via epithelial-to- mesenchymal transition (EMT). The central hypothesis is that EZH2 promotes SCCHN progression and recurrence by inducing rap1/EMT-mediated invasion and stemness; this critical role makes EZH2 an excellent treatment target. We will test our hypothesis by pursuing the following aims: #1) To investigate the mechanism by which EZH2 promotes invasion in SCCHN; #2) To define the mechanism of EZH2-induced treatment resistance; and #3) To evaluate the clinical relevance of EZH2 expression in human tissue. We will accomplish the objectives of this application using cell lines, 2D and novel 3D in vitro models, newly developed in vivo models of human SCCHN, and human tissue. The proposed studies will identify novel mechanisms through which rap1 integrates epigenetic reprogramming and EMT-mediated invasion, stemness and treatment resistance in SCCHN. Thus, our findings will facilitate the design of rational strategies to treat SCCHN.