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Date of Award

2011

Document Type

Thesis - Pacific Access Restricted

Degree Name

Master of Science (M.S.)

Department

Biological Sciences

First Advisor

Joanna S. Albala

First Committee Member

Lisa A. Wrischnik

Second Committee Member

Eric O. Thomas

Third Committee Member

Craig A. Vierra

Abstract

The active form of Vitamin D (VD3) has been shown to induce pro-apoptotic and anti-proliferative effects in several mammalian cancer cell types. The molecular mechanisms of tumor suppression, however, are not clearly understood. Previous research has shown that head and neck squamous cell carcinoma (HNSCC) responds to VD3. This thesis used both in vivo and in vitro models to examine the effect of VD3 in HNSCC. Former work in the Albala laboratory showed that hamsters that received systemic VD3 and topical treatment of 7,12-dimethylbenz(a)anthracene (DMBA) to the buccal pouch showed no or delayed carcinogenesis over the 14-week study compared to DMBA-only treated hamsters. This research further investigated the effect of VD3 in this hamster model. Using immunohistochemical (IHC) and western blot analysis, we demonstrate that systemic application of VD3to hamsters downregulates Rad51 expression in the buccal pouch and hinders the onset of tumor formation. Rad51 is a protein that plays a critical role in cell proliferation and homologous recombinational DNA repair. In the in vitro model, we show that Rad51 expression decreased in response to 100nM VD3 in HNSCC cell lines. The dose and time-dependence of VD3 on these cells was also examined. Western blot analysis and comet assay investigations confirmed that the SCC25 cell line is most sensitive to 100nM VD3 than to other doses tested, and that VD3 impairs the DNA-damage response. SiRNA and co-immunoprecipitation studies examined the potential of Chk 1 and p38 MAPK as upstream regulators of Rad51. Rad51 protein expression was found to be associated with early carcinogenesis from HNSCC cancer patients using IHC studies of human carcinomas from the oral cavity. This study focused on further identifying the role of Rad51 in response to VD3 in HNSCC.

Pages

101

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