EPS8 as a Driver of the Oral Cancer Initiating Cell Phenotype.

EPS8 作为口腔癌起始细胞表型的驱动因素。

• 批准号: 8722239
• 负责人: WILLIAM ANDREW YEUDALL
• 金额: $ 33.64万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722239
• 关键词: Affect; Automobile Driving; Binding Sites; Biology; CXC Chemokines; Cancer Cell Growth; Carcinogens; Cell Line; Cells; ChIP-on-chip; ChIP-seq; Clinical; Disease; EPS8 gene; Elasticity; Epidermal Growth Factor Receptor; Extracellular Matrix; Figs - dietary; Gene Combinations; Genes; Genetic Transcription; Goals; Growth Factor Receptors; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Integrins; Ions; Knowledge; Laboratories; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Mechanics; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mus; Mutagenesis; Neoplasm Metastasis; Normal tissue morphology; Oncogenes; Oral; Pathway interactions; Phenotype; Phosphorylation; Positioning Attribute; Property; Protein Isoforms; Quality of life; RNA Interference; Radiation therapy; Receptor Signaling; Recurrence; Refractory; Regulation; Reporting; Repression; Rivers; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stem cells; Structure of thyroid parafollicular cell; Surgical Management; Testing; Therapeutic; Tissues; Work; base; cancer cell; cancer stem cell; cell growth; cell motility; epithelial to mesenchymal transition; extracellular; improved; inhibitor/antagonist; keratinocyte; malignant mouth neoplasm; malignant phenotype; mortality; novel; oral carcinogenesis; overexpression; pluripotency; promoter; public health relevance; response; scaffold; self-renewal; therapeutic target; therapy resistant; transcription factor; tumor; tumor microenvironment; tumorigenic

DESCRIPTION (provided by applicant): Although major improvements have been made in chemotherapeutic, radiotherapeutic and surgical management of head and neck squamous cell carcinoma, morbidity and mortality from these lesions remain unacceptable. Moreover, in spite of major advances in therapy of other cancers, many head and neck cancers remain refractory to treatment with standard agents. The likelihood that subpopulations of cancer cells with self- renewal properties ("cancer stem cells" or cancer-initiating cells [CICs]) are responsible for resistance to therapy is becoming increasingly recognized, although little is known about the molecular pathways that determine the CIC phenotype. Our previous work identified EPS8, a mediator of growth factor receptor signaling, as being central to oral cancer cell growth and motility. We also found that EPS8 stimulates the expression of pluripotency-related transcription factors, and that binding sites for these exist within the EPS8 promoter. Moreover, we found that p63, a reported marker of keratinocyte stem cells, acts as a repressor of EPS8 expression, and that RNAi-mediated knockdown of p63 results in elevated levels of EPS8, promoting cell growth. This has led us to propose the hypothesis that elevated expression of EPS8 through relief of p63-mediated repression activates pathways promoting self-renewal and enhanced tumorigenic capacity. The proposed study has three objectives: first, to determine the mechanism through which p63 regulates EPS8; second, to define the role of EPS8 as a driver of the malignant phenotype of oral CICs; and, third, to understand how EPS8 expression and activity in oral CICs modulates their response to the microenvironment. Achieving these objectives will allow us to identify pathways responsible for the malignant properties of CICs that are likely to underpin tumor recurrence. Ultimately, this will uncover rational therapeutic targets to improve the quality of life of those affected by head and neck squamous cell carcinoma.

描述（由申请人提供）：尽管头颈部鳞状细胞癌的化疗、放疗和手术治疗已取得重大进展，但这些病变的发病率和死亡率仍然不可接受。此外，尽管在其他癌症的治疗方面取得了重大进展，但许多头颈癌仍然难以用标准药物治疗。具有自我更新特性的癌细胞亚群（“癌症干细胞”或癌症起始细胞[CIC]）负责对治疗的抗性的可能性正变得越来越被认识，尽管对决定CIC表型的分子途径知之甚少。我们以前的工作确定了EPS 8，生长因子受体信号传导的介质，作为口腔癌细胞生长和运动的中心。我们还发现，EPS 8刺激多能性相关的转录因子的表达，并且这些转录因子的结合位点存在于EPS 8启动子内。此外，我们发现，p63，角质形成细胞干细胞的标记物，作为EPS 8表达的阻遏物，并且RNAi介导的p63敲低导致EPS 8水平升高，促进细胞生长。这使我们提出了一个假设，即通过缓解p63介导的抑制来提高EPS 8的表达，从而激活促进自我更新和增强致瘤能力的途径。这项研究有三个目的：第一，确定p63调节EPS 8的机制;第二，确定EPS 8作为口腔CIC恶性表型驱动因素的作用;第三，了解EPS 8在口腔CIC中的表达和活性如何调节其对微环境的反应。实现这些目标将使我们能够确定负责CIC的恶性特性的途径，这些恶性特性可能是肿瘤复发的基础。最终，这将揭示合理的治疗目标，以提高质量 头颈部鳞状细胞癌患者的生命周期。