Role of PKCepsilon in Oral Cancer

摘要： 口腔鳞状细胞癌(口腔鳞状细胞癌)占全球50万例口腔鳞癌的大部分。 口腔和口咽。尽管在当地控制和生存方面的改善是通过 综合疗法的使用，口腔癌的总体5年生存率并没有提高 在过去的20年里有很大的变化。明确治疗后局部区域复发和远处转移是一种 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 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 结果表明：1)HNSCC(包括口腔和喉癌)中PKCepsilon显著升高； 通过siRNA靶向抑制PKCepsilon足以减少口腔中的细胞侵袭和运动 3)Rho GTP酶，特别是RhoA和RhoC位于PKCepsilon下游 PKCepsilon介导的细胞侵袭和运动所需的信号通路和4)LIM结构域激酶 2和stathmin，这两个参与细胞骨架动力学和细胞运动的蛋白质被鉴定为新的蛋白质。 PKCepsilon底物。我们的初步观察为PKCepsilon在疾病中的重要性建立了强有力的证据 在口腔鳞癌中建立侵袭性、高转移性的表型。我们建议广泛研究 PKCepsilon在口腔鳞癌中的生物学作用，我们将重点介绍PKCepsilon的分子机制 对PKCepsilon介导的RhoA和RhoC激活的机制进行了研究，并对其进行了剖析 PKC？介导的细胞运动信号网络，并确定选择的PKC？对以下各项必不可少的节点 口腔鳞状细胞癌中细胞的运动性。项目说明： 该项目旨在首次广泛研究PKCepsilon在 转移，口腔鳞状细胞癌的顽固性挑战。这些实验将为我们的 对癌细胞通过PKCepsilon信号转导的认识，将推动新疗法的开发 预防转移性口腔鳞癌的策略。

ABSTRACT: 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 PKC?-mediated cell motility signaling network and determine the select PKC? nodes that are indispensable for cell motility in oral SCC. PROJECT NARRATIVE: This project is designed to extensively examine for the first time the role of PKCepsilon in the development of metastasis, an 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.