Doctoral Dissertations

Date of Award

5-2007

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

David A. Gerard

Committee Members

Eric R. Carlson, Jack E. Gotcher, Darryl L. Millis

Abstract

Matrix metalloproteinases (MMP’s) and cathepsins are thought to play key roles in oral squamous cell carcinoma (OSCC) invasion and metastasis. Three OSCC human cell lines, BHY, HN and HSC-3, have been studied based on their reported ability to invade adjacent bone or metastasize to lymph nodes and/or distant organs. The working hypothesis of this study is that OSCC that demonstrate different actions have different proteolytic enzyme and gene expression profiles.

Immunocytochemistry and flow cytometry were used to determine the expression levels of certain proteolytic enzymes. Complementary DNA (cDNA) microarray technique was used to determine the gene expression profiles of each of the three OSCC cell lines.

The immunocytochemistry and flow cytometry results showed that the BHY cell line expresses MMP- 9 and extracellular matrix metalloproteinase inducer (EMMPRIN). The BHY cell line expressed 139 upregulated genes and 117 downregulated genes. The HN cell line expressed 214 upregulated and 262 downregulated genes. Finally, the HSC-3 cell line expressed 128 upregulated and 117 downregulated genes. There were 13 genes that were upregulated and 83 genes that were downregulated in all three OSCC cell lines. Eight pathways were upregulated and 3 pathways were downregulated in the BHY cell line. In the HN cell line 10 pathways were upregulated and 9 were downregulated. Finally, in the HSC-3 cell line 3 pathways were upregulated and 6 pathways were downregulated.

MMP-1, MMP-9 and EMMPRIN appear to play a role in the invasion of OSCC to bone. KIAA, was upregulated in our study in the HN cell line. Upregulation of KIAA may be involved in the late stage of OSSC. PAM gene was the only downregulated gene in the HN cell line. The TM4SF10 gene was downregulated in all three OSCC cell lines. The COL1A2 and COL4A1 genes were upregulated in the HSC-3 cell line and they may cause the lymph node metastasis of OSCC. Based on this study OSCC involves multiple molecular genetic events that take place in many chromosomes and genes. Upregulation of the Jak-STAT signaling pathway may be involved in bone invasion of OSCC. The MAPK signaling pathway was upregulated in all three OSCC cell lines.

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