Date Approved

5-2017

Document Type

Thesis

Degree Name

Master of Science in Molecular Pathology and Immunology

Department

Molecular Biology

College

Graduate School of Biomedical Sciences

First Advisor

Salvatore Caradonna, PhD

Committee Member 1

Ilana Stroke, PhD

Committee Member 2

Jim Beasley, PhD

Committee Member 3

Rachael Siegel Alcantara, PhD

Subject(s)

Cadherins; Zinc Finger E-box-Binding Homeobox 1; Endometrial Neoplasms; Histone Deacetylase Inhibitors

Disciplines

Cancer Biology | Cell Biology | Female Urogenital Diseases and Pregnancy Complications | Laboratory and Basic Science Research | Medicine and Health Sciences | Molecular Biology | Molecular Genetics | Neoplasms

Abstract

Epithelial to mesenchymal transition (EMT) is the process in which cells lose their epithelial structure during gastrulation. This process also affects the migration and movement of tumor cells and promotes invasion and metastases of endometrial carcinomas. Down-regulation of E-cadherin (CDH1) by transcription factors is the key target of EMT modulators and is achieved mainly by ZEB1 (zinc finger E-box binding homeobox 1). Current research looking at restoration of E-cadherin expression in vitro involves the use of small molecules such as histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors. Trichostatin A (TSA) and small interfering ribonucleic acid (siRNA) are tools that can be used to induce CDH1 activity.

To identify a cell line that is suitable for testing novel compounds and capable of increasing E-cadherin expression via ZEB1 inhibition, two uterine adenocarcinoma cell lines (AN3CA and SK-UT-1B), stably transfected with an E-cadherin promoter reporter gene, were characterized using various assays. Novel, small molecule compounds were tested on a colon cancer cell line (SW620/CDH1-NLuc) and showed enhancement of CDH1 reporter activity. In this thesis research several assays were performed to test our hypothesis that modulating ZEB1 using small molecules may lead to an increase in the expression of E-cadherin in endometrial cancers and CDH1 responsiveness to the small molecules in endometrial cancer cell lines will be observed.

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