Role of EZH2 in Invasion and Migration in the Oral Mucosa

EZH2 在口腔粘膜侵袭和迁移中的作用

基本信息

批准号：
8893946
负责人：
Nisha J D'Silva
金额：
$ 34.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893946
关键词：
Apoptosis Biological Markers Cell Line Cells Cisplatin Data Development Diagnosis Disease Distant E-Cadherin EZH2 gene Epigenetic Process Epithelial Exhibits Figs - dietary Genes Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Immigration In Vitro Lesion by Stage Life Link Malignant Neoplasms Mediating Mesenchymal Methylation Modeling Molecular Mus Natural regeneration Neoplasm Metastasis Nuclear Nuclear Translocation Oral mucous membrane structure Patients Pilot Projects Process Publishing Quality of life Radiation Recurrence Rehabilitation therapy Relapse Research Resistance Resistance development Role Site Stem cells Testing Tissue Microarray Treatment Cost base cancer stem cell chemotherapy chorioallantoic membrane clinically relevant design effective therapy epithelial to mesenchymal transition global health human tissue improved in vitro Model in vivo in vivo Model loss of function membrane model mortality novel novel strategies prevent public health relevance stemness three-dimensional modeling treatment strategy tumor

项目摘要

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.

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基于机制的新策略。 SCCHN 患者经常对治疗产生耐药性，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，四十多年来一直没有新的治疗方法，这凸显了对新治疗策略的需要。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以及侵袭性细胞在肿瘤中重新增殖并扩散到远处的部位 “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调节，因此针对表观遗传机制的治疗策略非常重要。拟议的研究重点关注一种主要的表观遗传调控机制，该机制通过上皮间质转化（EMT）整合侵袭和干性介导的治疗耐药性。中心假设是 EZH2 通过诱导 rap1/EMT 介导的侵袭和干性来促进 SCCHN 进展和复发；这一关键作用使 EZH2 成为极佳的治疗靶点。我们将通过追求以下目标来检验我们的假设：#1）研究EZH2促进SCCHN侵袭的机制； #2) 明确EZH2诱导的治疗抵抗的机制； #3) 评估人体组织中 EZH2 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、新开发的人类 SCCHN 体内模型和人体组织来实现此应用的目标。拟议的研究将确定 rap1 在 SCCHN 中整合表观遗传重编程和 EMT 介导的侵袭、干性和治疗耐药性的新机制。因此，我们的研究结果将有助于设计合理的 SCCHN 治疗策略。