Role of Plakophilin-1 in HNSCC

描述(由申请人提供)：了解头颈部鳞状细胞癌(HNSCC)进展过程中的分子变化对于预测临床结果和开发有效的治疗方法至关重要。血小板亲和素-1是Armadillo(ARM)蛋白家族的成员，Armadillo(ARM)蛋白是细胞-细胞黏附连接的结构组件，称为桥粒。此外，在核中还发现了PLAK-1，其功能尚不清楚。β-连环蛋白是ARM家族中研究较多的一个成员，它通常在质膜上与黏附的细胞-细胞黏附复合体结合，但也在细胞核中发现，它是Wnt信号通路中的转录调节因子，在结肠癌中发挥关键作用。本研究提供的数据表明，不仅在HNSCC中PLAK-1蛋白的表达减少，而且在细胞系中PARK-1的表达减少导致细胞在体外的运动能力增加。这个项目的中心假设是，与β-连环蛋白类似的PLAKAPILIN-1在细胞-细胞黏附和基因表达中发挥作用，这些细胞事件的转变在HNSCC的恶性进展中起着关键作用。这项拟议工作的目标是通过证明亲血小板蛋白-1的表达缺失会改变与肿瘤进展相关的基因的表达，从而确定嗜血小板蛋白-1在HNSCC中的核作用。这些研究的具体目的是：(1)确定血小板亲和素-1转位到细胞核的机制；(2)确定血小板亲和素-1/TLS复合体的核功能；(3)确定血小板亲和素-1靶基因在HNSCC进展中的作用。这项工作将得到已经为该项目开发的两种工具的极大帮助：一种是高度特异的抗噬菌体亲和素-1的单抗，另一种是可以在细胞中外源表达的可激活形式的胞膜亲和素-1。明确血小板亲和素-1的核功能将为寻找新的HNSCC预后标志物奠定基础，也将为治疗HNSCC的新治疗策略奠定潜在的靶点。

DESCRIPTION (provided by applicant): Understanding molecular changes in progression of head and neck squamous cell carcinoma (HNSCC) is essential for predicting clinical outcome and for developing effective therapies for treating the disease. Plakophilin-1 is a member of the Armadillo (Arm) protein family that is a structural component of the cell-cell adhesion junction known as the desmosome. In addition, plakophilin-1 is found in the nucleus, where its function is unknown. A well-studied member of the Arm family, ?-catenin, normally associates at the plasma membrane with the adherens cell-cell adhesion complex but also is found in the nucleus where it is a transcriptional regulator in the Wnt signaling pathway and plays a critical role in colon cancer. Data presented in this proposal show that not only is plakophilin-1 protein expression reduced in HNSCC, reducing plakophilin-1 expression in cell lines leads to increased cell motility in vitro. The central hypothesis for this project is that plakophilin-1, similar to ?-catenin, plays roles in both cell-cell adhesion and gene expression and that a shift in these cellular events plays a critical role in the malignant progression of HNSCC. The goal for the proposed work is to define the nuclear role for plakophilin-1 in HNSCC by showing that loss of plakophilin-1 expression alters the expression of genes relevant to tumor progression. The specific aims are (1) to determine the mechanisms of plakophilin-1 translocation to the nucleus, (2) to determine the nuclear function of the plakophilin-1/TLS complex, and (3) to determine the role of plakophilin-1 target genes in HNSCC progression. This work will be greatly aided by two tools already developed for the project: a highly specific monoclonal antibody to plakophilin-1 and an activatable form of plakophilin-1 that can be exogenously expressed in cells. Defining the nuclear function of plakophilin-1 will lay the ground work for identifying new prognostic markers for HNSCC and also potential targets for novel therapeutic strategies for treating the disease.