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

描述(申请人提供)：尽管头颈部鳞状细胞癌在化疗、放射治疗和外科治疗方面取得了重大进展，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，但许多头颈部癌症仍然对标准药物治疗无效。尽管人们对决定CIC表型的分子途径知之甚少，但具有自我更新特性的癌细胞亚群(“癌症干细胞”或癌症启动细胞[CICs])对治疗耐药的可能性正日益被认识到。我们之前的工作发现，Eps8是生长因子受体信号转导的中介，对口腔癌细胞的生长和运动具有中心作用。我们还发现Eps8刺激多能性相关转录因子的表达，并且这些转录因子的结合位点存在于Eps8启动子中。此外，我们发现P63是角质形成细胞干细胞的标志物，它抑制了Eps8的表达，而RNAi介导的P63基因敲除会导致Eps8水平升高，从而促进细胞生长。这导致我们提出假设，通过解除p63介导的抑制，Eps8的表达增加激活了促进自我更新和增强致瘤能力的途径。这项拟议的研究有三个目标：第一，确定P63调控Eps8的机制；第二，确定Eps8作为口腔CICs恶性表型的驱动因素；第三，了解Eps8在口腔CICs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导致CICs恶性特性的途径，这些途径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活质量。

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.