Role of PKCepsilon in Oral Cancer

描述（由申请人提供）：口腔鳞状细胞癌（Oral SCC）占全球50万例口腔和口咽部癌症的大部分。虽然使用联合治疗方法可以改善局部控制和生存率，但在过去20年中，口腔癌的总体5年生存率并没有显著提高。最终治疗后局部复发和远处转移是口腔鳞状细胞癌患者发病率和死亡率的主要原因。这一临床问题促使我们确定导致口腔鳞状细胞癌复发和转移的遗传决定因素。在初步研究中，我们证明：1) PKCepsilon在包括口腔和喉部SCC在内的HNSCC中显著升高；2)通过siRNA靶向抑制PKCepsilon，足以降低口腔和喉部SCC中的细胞侵袭和运动；3)Rho gtpase，特别是RhoA和RhoC，位于PKCepsilon信号通路的下游，是PKCepsilon介导的细胞侵袭和运动所必需的；4)LIM结构域激酶2和Stathmin，这两种蛋白参与细胞骨架动力学和细胞运动。被鉴定为新的PKCepsilon底物。我们的初步观察为PKCepsilon在口腔SCC中建立侵袭性、高度转移表型的重要性建立了强有力的案例。我们建议广泛研究PKCepsilon在口腔SCC中的生物学作用，特别是我们将重点研究PKCepsilon失调的分子机制，PKCepsilon介导的RhoA和RhoC激活的机制，解剖PKC5介导的细胞运动信号网络，确定口腔SCC中细胞运动不可或缺的PKC5节点。公共卫生相关性：该项目旨在首次广泛研究PKCepsilon在口腔鳞状细胞癌转移发展中的作用，这是一种顽固性挑战。这些实验将为我们通过PKCepsilon了解癌细胞信号传导提供重大进展，并将推动针对转移性口腔鳞状细胞癌的新治疗策略的发展。

DESCRIPTION (provided by applicant): Oral squamous cell carcinoma (oral SCC) accounts for most of the 500,000 worldwide incident cancers of the oral cavity and oropharynx. Although improvements in local control and survival have been achieved with the use of combined modality therapies, the overall 5 year survival rate for oral cancers have not improved significantly over the past 20 years. Local-regional relapse and distant metastasis after definitive therapy are a major cause of morbidity and mortality in oral SCC patients. This clinical problem has prompted us to identify genetic determinants that contribute to oral SCC relapse and metastasis. In preliminary studies, we demonstrate that: 1) PKCepsilon is significantly elevated in HNSCC, including oral and laryngeal SCC, 2) targeted inhibition of PKCepsilon, through siRNA , was sufficient to decrease cell invasion and motility in oral and laryngeal SCC, 3) Rho GTPases, specifically RhoA and RhoC, are downstream of the PKCepsilon signaling pathway and required for PKCepsilon-mediated cell invasion and motility, and 4) LIM domain kinase 2 and Stathmin, two proteins that are involved in cytoskeleton dynamics and cell motility, are identified as novel PKCepsilon substrates. Our preliminary observations build a strong case for the importance of PKCepsilon in establishing an aggressive, highly metastatic phenotype in oral SCC. We propose to extensive study the biological role of PKCepsilon in oral SCC, specifically we will focus on the molecular mechanism of PKCepsilon dysregulation, on the mechanism of PKCepsilon-mediated RhoA and RhoC activation, and to dissect the PKC5-mediated cell motility signaling network and determine the select PKC5 nodes that are indispensable for cell motility in oral SCC. PUBLIC HEALTH RELEVANCE: This project is designed to extensively examine for the first time the role of PKCepsilon in the development of metastasis, a recalcitrant challenge in oral SCC. These experiments will provide significant advance in our knowledge of cancer cell signaling through PKCepsilon and will advance the development of a novel treatment strategies against metastatic oral squamous cell carcinoma.