Role of PKCepsilon in Oral Cancer

描述(申请人提供)：口腔鳞状细胞癌(口腔鳞状细胞癌)占全球500,000例口腔和口咽癌中的大部分。虽然综合治疗方案的使用改善了口腔癌的局部控制和生存率，但在过去的20年里，口腔癌的总体5年生存率并没有显著提高。明确治疗后局部复发和远处转移是口腔鳞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基因决定因素。在初步研究中，我们发现：1)PKCepsilon在口腔和喉鳞状细胞癌中显著升高，2)通过siRNA靶向抑制PKCepsilon足以减少口腔和喉癌的细胞侵袭和运动，3)Rho GTP酶，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，以及4)Lim结构域激酶2和stathmin，两种参与细胞骨架动力学和细胞运动的蛋白质，被确定为新的PKCepsilon底物。我们的初步观察为PKCepsilon在口腔鳞状细胞癌中建立侵袭性、高转移性表型的重要性建立了强有力的证据。我们建议广泛研究PKCepsilon在口腔鳞状细胞癌中的生物学作用，特别是PKCepsilon失调的分子机制，PKCepsilon介导的RhoA和RhoC激活机制，并剖析PKC5介导的细胞运动信号网络，确定口腔鳞状细胞癌中细胞运动所必需的PKC5节点。公共卫生相关性：该项目旨在首次广泛研究PKCepsilon在口腔鳞状细胞癌顽固性挑战-转移发展中的作用。这些实验将对我们通过PKCepsilon传递癌细胞信号的知识提供重大进展，并将推动开发一种新的治疗策略来对抗转移性口腔鳞癌。

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.