Date of Award

9-23-2010

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

John Geibel

Second Advisor

Michael Centrella

Third Advisor

Dianne Duffey

Abstract

TGF-β RECEPTOR III ENHANCES TGF-β AND NF-κB SIGNALING IN HEAD AND NECK SQUAMOUS CELL CARCINOMA Frederick Wang, Amy Schell, Xinping Yang, Jeffrey Burnett, Arun Pattatheyil, Jay Friedman, Zhong Chen, Carter Van Waes. Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD. (Sponsored by Dr. Dianne Duffey. Otolaryngology, Yale Department of Surgery) Alterations in the function of the nuclear factor-β (NF-κB) and transforming growth factor-β (TGF-β) signaling pathways have been implicated in the development and progression of head and neck squamous cell carcinoma (HNSCC). TGF-β receptor III (TGFBR3) is a TGF-β superfamily co-receptor that has been characterized as a tumor suppressor gene and is downregulated in several types of human cancers. HNSCC cell lines expressing low levels of wild-type p53 had decreased TGFBR3 mRNA transcripts relative to human epidermal keratinocytes (HEKa) and cell lines expressing mutant p53, leading us to investigate the role of TGFBR3 in tumorigenesis. We established a stable cell line overexpressing TGFBR3 (UM-SCC 1-TGFBR3). We demonstrate that TGFBR3 increased TGF-β signaling through stimulation of Smad-dependent 3TP reporter activity and upregulation of PAI-1 and p21Cip1 expression. TGFBR3 also increased NF-κB and AP-1 reporter activity, downstream IL-6 and IL-8 cytokine production, and p65 and p38 MAPK phosphorylation. Furthermore, TGFBR3 induced a microspike/filopodia-like phenotype in HNSCC cells and reduced cell proliferation and migration in vitro. In this first study examining TGFBR3 in HNSCC, we demonstrate that TGFBR3 expression increases TGF-β and NF-κB signaling and reduces cell proliferation and migration in HNSCC.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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