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）进展中的分子变化对于预测临床结局和开发治疗该疾病的有效疗法至关重要。Plakophilin-1是Armadillo（Arm）蛋白家族的成员，其是称为桥粒的细胞-细胞粘附连接的结构组分。此外，plakophilin-1在细胞核中发现，其功能尚不清楚。Arm家族的一个被充分研究的成员β-连环蛋白通常在质膜上与粘附细胞-细胞粘附复合物结合，但也在细胞核中发现，在细胞核中它是Wnt信号传导途径中的转录调节因子，并在结肠癌中起关键作用。该提案中提供的数据表明，不仅HNSCC中的血小板生成素-1蛋白表达降低，细胞系中血小板生成素-1表达的降低导致体外细胞运动性增加。该项目的中心假设是，plakophilin-1，类似于β-连环蛋白，在细胞-细胞粘附和基因表达中起作用，并且这些细胞事件的转变在HNSCC的恶性进展中起关键作用。这项工作的目标是通过显示plakophilin-1表达的丧失改变了与肿瘤进展相关的基因的表达来确定plakophilin-1在HNSCC中的核作用。具体目的是（1）确定plakophilin-1易位到细胞核的机制，（2）确定plakophilin-1/TLS复合物的核功能，和（3）确定plakophilin-1靶基因在HNSCC进展中的作用。这项工作将大大有助于两个工具已经开发的项目：一个高度特异性的单克隆抗体plakophilin-1和一个可激活形式的plakophilin-1，可以在细胞中外源表达。 确定plakophilin-1的核功能将为确定HNSCC的新预后标志物以及治疗该疾病的新治疗策略的潜在靶点奠定基础。

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, beta-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 beta-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 2 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.