Role of PKCepsilon in Oral Cancer

描述（由申请人提供）：口腔鳞状细胞癌（口腔SCC）占全世界50万口腔和口咽癌发病率的大部分。虽然局部控制和生存率的改善已经实现了与使用的综合治疗，口腔癌的总体5年生存率在过去的20年中没有显着改善。确定性治疗后局部复发和远处转移是口腔鳞癌患者发病和死亡的主要原因。这一临床问题促使我们确定遗传因素，有助于口腔鳞状细胞癌复发和转移。在初步研究中，我们证明：1）PKC β在HNSCC（包括口腔和喉SCC）中显著升高，2）通过siRNA靶向抑制PKC β足以降低口腔和喉SCC中的细胞侵袭和运动性，3）Rho GTP酶，特别是RhoA和RhoC，是PKC β信号通路的下游，并且是PKC β介导的细胞侵袭和运动性所需的，LIM结构域激酶2和Stathmin是两种参与细胞骨架动力学和细胞运动的蛋白质，被鉴定为新的PKC β底物。我们的初步观察建立了一个强有力的情况下，在口腔鳞状细胞癌中建立一个积极的，高转移表型的PKC β的重要性。我们建议广泛研究PKC 5在口腔SCC中的生物学作用，特别是我们将专注于PKC 5失调的分子机制，PKC 5-介导的RhoA和RhoC激活的机制，并剖析PKC 5-介导的细胞运动信号网络，并确定选择PKC 5节点是必不可少的细胞运动在口腔SCC中。公共卫生相关性：该项目旨在首次广泛研究PKC β在转移发展中的作用，这是口腔SCC的一个巨大挑战。这些实验将提供显着的进步，在我们的知识癌细胞信号通过PKC β，并将推进发展一种新的治疗策略，对转移性口腔鳞状细胞癌。

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.