Date of Award

5-1-2011

Degree Type

Dissertation

University or Center

Clark Atlanta University(CAU)

School

School of Arts and Sciences

Degree Name

Ph.D.

Department

Biology

First Advisor

Dr. Valerie Odero-Marah

Second Advisor

Dr. Shafiq Khan

Third Advisor

Dr. Cimona Hinton

Abstract

Snaill (Snail) transcription factor induces Epithelial Mesenchymal Transition (EMT), in which epithelial cells down-regulate cell adhesion genes such as E-cadherin and up-regulate mesenchymal genes such as vimentin, leading to increased invasion and migration. Maspin is a putative tumor suppressor that is down-regulated in breast and prostate cancer and has been associated with decreased cell motility, while Snail is increased in breast cancer and associated with increased tumor motility and invasion. Very little is known about the role of Snail in cellular adhesion to the extracellular matrix (ECM) and its role in regulation of maspin expression has not been explored. We hypothesized that Snail will lead to decreased cellular adhesion to the extracellular matrix through integrin regulation, concomitant with increased cell migration. Our studies showed that Snail decreases cell adhesion to fibronectin (FN) and collagen I (CGN) matrix through inhibition of cL5 (fibronectin receptor), c~2 (collagen receptor), ~3 1 integrins, while migration to FN and CON was increased. We have also identified an inverse relationship between Snail and rnaspin in normal prostate epithelial cells and prostate cancer cells and shown for the first time that Snail can inhibit maspin expression.

This work utilized normal prostate epithelial cells (PrEC), androgen-dependent LNCaP cells, androgen-independent C4-2, DU145, 22Rvl, ARCaP and PC3 prostate cancer cell lines. Cells with either the endogenous, overexpression or knockdown of the Snail transcription factor were utilized to observe the role of Snail in cell adhesion and migration and to establish its molecular mechanism(s) of action. We have provided direct evidence that the Snail transcription factor negatively impacts prostate cancer cell adhesion and migration to fibronectin and collagen matrices. This activity was regulated through integrins and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we have shown that Snail negatively regulates maspin expression by inhibiting activity at the maspin promoter.

Collectively, these studies define a new role for Snail in cell adhesion to the ECM. Therefore, targeting of Snail may be useful to re-induce expression of maspin putative tumor suppressor, increase cell adhesion to ECM, decrease cell migration and prevent prostate cancer tumor progression and metastasis.

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