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

• 批准号: 8743202
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743202
• 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

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新的基于机制的策略。SCCHN患者往往对治疗产生耐药性，从而导致肿瘤复发。因此，几乎一半的SCCHN患者在确诊后五年内死亡。尽管前景黯淡，但四十多年来一直没有新的治疗方法，这强调了新的治疗策略的必要性。了解头颈癌的分子机制对有效治疗至关重要。肿瘤起始细胞或干细胞和侵袭性细胞重新填充肿瘤并扩散到远处