Role of EZH2 in Invasion and Migration in the Oral Mucosa

描述（由申请人提供）：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患者通常会对治疗产生耐药性，从而导致肿瘤复发。因此，几乎一半的SCCHN患者在诊断后五年内死亡。尽管前景黯淡，但40多年来一直没有新的治疗方法，这突出了对新治疗策略的需求。了解调节头颈癌的分子机制对于有效治疗至关重要。肿瘤起始细胞或干细胞和侵袭性细胞在肿瘤发生后重新填充肿瘤并扩散到远处。 “成功”的治疗由于侵袭、复发和扩散所需的细胞可塑性主要受表观遗传学调节，因此靶向表观遗传机制的治疗策略很重要。拟议的研究集中在一个主要的表观遗传调控机制，整合入侵，干细胞介导的治疗抗性通过上皮间质转化（EMT）。核心假设是EZH 2通过诱导rap 1/EMT介导的侵袭和干性来促进SCCHN的进展和复发;这一关键作用使EZH 2成为极好的治疗靶点。我们将通过追求以下目标来测试我们的假设：#1）研究EZH 2促进SCCHN中侵袭的机制; #2）定义EZH 2诱导的治疗抗性的机制;以及#3）评估EZH 2在人组织中表达的临床相关性。我们将使用细胞系、2D和新型3D体外模型、新开发的人SCCHN体内模型和人组织来实现本申请的目的。拟议的研究将确定rap 1整合SCCHN中表观遗传重编程和EMT介导的入侵，干性和治疗抗性的新机制。因此，我们的研究结果将有助于设计合理的策略来治疗SCCHN。

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.