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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-GH (03))
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Shirazi, Yasaman
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University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
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Vigneswaran, Nadarajah; Wu, Jean; Song, Anren et al. (2011) Hypoxia-induced autophagic response is associated with aggressive phenotype and elevated incidence of metastasis in orthotopic immunocompetent murine models of head and neck squamous cell carcinomas (HNSCC). Exp Mol Pathol 90:215-25
Nagaraj, Nagathihalli S; Zacharias, Wolfgang (2007) Cigarette smoke condensate increases cathepsin-mediated invasiveness of oral carcinoma cells. Toxicol Lett 170:134-45
Vigneswaran, Nadarajah; Baucum, Darryl C; Wu, Jean et al. (2007) Repression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not its receptors during oral cancer progression. BMC Cancer 7:108
Nagaraj, Nagathihalli S; Vigneswaran, Nadarajah; Zacharias, Wolfgang (2007) Hypoxia inhibits TRAIL-induced tumor cell apoptosis: involvement of lysosomal cathepsins. Apoptosis 12:125-39
Vigneswaran, Nadarajah; Wu, Jean; Nagaraj, Nagathihalli et al. (2006) Silencing of cystatin M in metastatic oral cancer cell line MDA-686Ln by siRNA increases cysteine proteinases and legumain activities, cell proliferation and in vitro invasion. Life Sci 78:898-907
Nagaraj, Nagathihalli S; Beckers, Simone; Mensah, John K et al. (2006) Cigarette smoke condensate induces cytochromes P450 and aldo-keto reductases in oral cancer cells. Toxicol Lett 165:182-94
Vigneswaran, Nadarajah; Beckers, Simone; Waigel, Sabine et al. (2006) Increased EMMPRIN (CD 147) expression during oral carcinogenesis. Exp Mol Pathol 80:147-59
Nagaraj, Nagathihalli S; Vigneswaran, Nadarajah; Zacharias, Wolfgang (2006) Cathepsin B mediates TRAIL-induced apoptosis in oral cancer cells. J Cancer Res Clin Oncol 132:171-83
Vigneswaran, Nadarajah; Wu, Jean; Nagaraj, Nagathihalli et al. (2005) Differential susceptibility of metastatic and primary oral cancer cells to TRAIL-induced apoptosis. Int J Oncol 26:103-12
Wickramasinghe, Nalinie S; Banerjee, Kasturi; Nagaraj, Nagathihalli S et al. (2005) Hypoxia alters cathepsin B / inhibitor profiles in oral carcinoma cell lines. Anticancer Res 25:2841-9

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