ROLE OF CATHEPSINS IN ORAL CANCER INVASION AND METASTASI

口腔癌是世界上最常见的10种癌症之一，据估计，美国每年新增3万例口腔癌病例。组织学上，几乎90%的口腔癌是鳞状细胞癌(SCC)，包括疣状癌和基底细胞样鳞癌的亚型。越来越多的证据表明，溶酶体组织蛋白B、D和L的表达增加和亚细胞定位改变促进了肿瘤的局部侵袭和区域/远处转移。这一假设是：具有不同局部侵袭特性和转移潜能的口腔癌在组织蛋白B、D和L的表达模式上存在明显的定性和定量差异，在分子水平上抑制这些组织蛋白将减少或消除这些恶性特性。该提案的具体目的是：具体目标1：确定组织蛋白酶B、D和L在口腔癌中的表达模式与其临床病理参数和组织学特征的关系。特定目的2：通过细胞内表达的核酶抑制口腔鳞癌细胞系中组织蛋白酶的表达，并在动物模型中分析这些细胞对侵袭和转移行为的影响。具体目的3：在转化的角质形成细胞中获得特定组织蛋白酶蛋白的过表达，并在动物模型中测试这些细胞获得性侵袭和/或转移表型的诱导。本实验旨在探讨组织蛋白酶B、D、L在口腔癌中的表达模式与口腔癌各亚型的组织学特征及临床表现之间的关系。这些研究还将通过核酶介导的组织蛋白抑制和重组组织蛋白基因表达方法来研究这些酶在侵袭和转移中的作用，这两种方法都应用于细胞培养和动物模型。组织蛋白酶B、D和L在口腔癌进展中的作用相关信息将成为设计治疗方案的基础，以在分子水平上抑制它们的表达，从而抑制癌症进展。

Oral cancer is one of the 10 most frequent cancers worldwide, with an estimated 30,000 new cases being diagnosed in the U.S. every year. Histologically almost 90 percent of oral cancers are squamous cell carcinomas (SCC), which include the subtypes of verrucous carcinoma and basaloid squamous cell carcinoma. There is increasing evidence to suggest that local invasion and regional/distant metastasis of carcinomas are facilitated by increased expression and altered subcellular localization of lysosomal cathepsins B, D and L. The Hypothesis of this proposal is: Oral carcinomas with different local invasive properties and metastatic potentials possess distinct qualitative and quantitative differences in their expression patterns of cathepsin B, D and L. The inhibition of such cathepsins on the molecular level will diminish, or abolish, these malignant properties. The Specific Aims of the proposal are: Specific Aim 1: To determine the relationship of the expression patterns of cathepsins B, D, and L in oral carcinomas and their clinicopathologic parameters and histological characteristics. Specific Aim 2: To inhibit cathepsin expression in oral squamous cell carcinoma cell lines by intracellularly expressed ribozymes, and to analyze the consequences on invasive and metastatic behavior of these cells in an animal model. Specific Aim 3: To obtain overexpression of selected cathepsin proteins in transformed keratinocytes cells, and to test for induction of acquired invasive and/or metastatic phenotypes in these cells in an animal model. These experiments are designed to correlate the expression patterns of cathepsin B, D, L in oral cancer with the histological characteristics and clinical findings of the carcinoma subtypes. These studies will also examine the role of these enzymes in invasion and metastasis by employing ribozyme- mediated cathepsin inhibition as well as recombinant cathepsin gene expression approaches, both being applied in cell culture and in an animal model. The information correlating the functions of cathepsins B, D and L in oral cancer progression will be the basis for the design of therapeutic modalities to inhibit their expression, and thus cancer progression, on the molecular level.