Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Barbara Boyan
Second Advisor
Zvi Schwartz
Third Advisor
Jennifer Koblinski
Fourth Advisor
Christopher Lemmon
Fifth Advisor
Nastassja Lewinski
Abstract
Laryngeal cancer is the most common type of head and neck cancer and is associated with poor prognosis due to common delayed diagnoses. The sex disparities associated with laryngeal cancer are constantly growing, as the risk of malignancy in males is continually increasing compared to women. Due to the high chance of late-stage diagnosis requiring aggressive treatments, there is a high demand for less aggressive treatment options and early-stage diagnostic markers. The apparent sex disposition of the larynx, the correlation between sex hormones, and the risk of malignancy in aging men suggest that estrogen may play a role in laryngeal cancer tumorigenesis. The studies in this thesis propose that estrogen receptors, specifically estrogen receptor alpha 66, can be used as a diagnostic and prognostic marker for laryngeal cancer, similar to clinical studies in breast cancer. Based on previous studies, vitamin D3 may be a promising anticancer agent due to its inhibitory effects on cell proliferation and survival in various cancers. Vitamin D3 is metabolized in the liver into its circulating form, 25(OH)D3, which is further metabolized into the active metabolites 1α,25(OH)2D3 or 24R,25(OH)2D3. 24R,25(OH)2D3 has been proposed as a therapeutic agent for some cancers as opposed to the more widely investigated metabolite 1α,25(OH)2D3 due to its lack of calciotropic effects. 24R,25(OH)2D3 has been shown to activate several membrane-associated signaling pathways, some of which overlap with 17b-estradiol (E2) signaling through ERa36, a splice variant of ERa. The overall hypothesis of this thesis was that 24R,25(OH)2D3 can regulate laryngeal cancer tumorigenesis and that this tumorigenicity is partly correlated by ERa isoforms. This hypothesis will be tested by three aims. Specific aim 1: Determine the regulatory effect of 24R,25(OH)2D3 on markers of laryngeal cancer progression in ERα66 positive versus ERα66 negative laryngeal cancer cells in vitro. Specific Aim 2: Determine the mechanisms involved in the effect of 24R,25(OH)2D3 on markers of laryngeal cancer progression in vitro. Specific Aim 3: Examine the effect of 24R,25(OH)2D3 on laryngeal cancer tumor growth and metastasis in vivo.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-7-2024