ROLE OF CATHEPSINS IN ORAL CANCER INVASION AND METASTASI

口腔癌是全球10种最常见的癌症之一，美国每年估计有30，000例新病例被诊断出来。 组织学上几乎90%的口腔癌是鳞状细胞癌（SCC），其包括疣状癌和基底样鳞状细胞癌的亚型。 越来越多的证据表明，溶酶体组织蛋白酶B、D和L的表达增加和亚细胞定位改变促进了癌的局部侵袭和区域/远处转移。 本研究的假设是：不同局部浸润性和转移潜能的口腔癌组织蛋白酶B、D和L的表达模式存在明显的质和量的差异。 在分子水平上抑制这种组织蛋白酶将减少或消除这些恶性性质。 具体目的1：明确组织蛋白酶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。具体目标二：目的：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其对这些细胞侵袭和转移行为的影响。 具体目标3：在转化的角质形成细胞中获得选定的组织蛋白酶蛋白的过表达，并在动物模型中测试这些细胞中获得性侵袭和/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亚型的组织学特征和临床表现之间的关系。 这些研究还将通过采用核酶介导的组织蛋白酶抑制以及重组组织蛋白酶基因表达方法来检查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中。 与组织蛋白酶B、D和L在口腔癌进展中的功能相关的信息将是在分子水平上设计抑制其表达并因此抑制癌症进展的治疗方式的基础。

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.