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STAT3 in EGF Receptor-Mediated Fibroblast and Human Prostate Cancer Cell Migration, Invasion and Apoptosis.

Zhou, Weixin (2006) STAT3 in EGF Receptor-Mediated Fibroblast and Human Prostate Cancer Cell Migration, Invasion and Apoptosis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Growth factor-induced migration is a rate-limiting step in tumor invasiveness. The molecules that regulate this cellular behavior would represent novel targets for limiting tumor cell progression. Epidermal growth factor (EGF) receptor (EGFR)-mediated motility, present in both autocrine and paracrine modes in prostate carcinomas, requires de novo transcription to persist over times greater than a few hours. Therefore, we sought the specific signaling pathways that directly alter cellular transcription. We confirmed that STAT3 directly associates with, and is activated by EGFR in DU-145 and PC3 human prostate carcinoma cells in addition to the model NR6 fibroblast cell line. This correlated with electrophoretic motility shift of STAT3-selective oligonucleotides. Inhibition of STAT3 activity by antisense or siRNA down-regulation or expression of a dominant-negative construct limited cell motility as determined by an in vitro wound healing assay and invasiveness through a matrix barrier. The expression of constitutively activated STAT3 in the absence of EGF did not increase the migration. Together these data indicate that STAT3 is necessary but not sufficient for EGFR-mediated migration. An initial gene array detected a number of candidate operative molecules; the protein levels of both ENA/VASP, a repressor of cell motility, and caspase 3, a nexus of apoptotic signaling, were down regulated by EGF in a STAT3-dependent manner. Preliminary data show that EGF requires STAT3 functioning to inhibit the induction of apoptosis in the two human prostate cancer cell lines. This suggests that STAT3 signaling may be contributing to tumor progression in a second manner by rendering the cells resistant to death. Together, the sum of these findings suggest that STAT3 signaling may be a new target for both limiting prostate tumor cell invasion and enabling the tumor cells to be killed.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhou, Weixinwez7@pitt.eduWEZ7
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberWells, Alanwellsa@msx.upmc.eduAHW6
Committee MemberGrandis, Jennifer Rjgrandis@pitt.eduJGRANDIS
Committee MemberLuo,
Committee MemberZarnegar, Rezarezazar@pitt.eduREZAZAR
Committee MemberSmithgall, Thomastsmithga@pitt.eduTSMITHGA
Date: 29 September 2006
Date Type: Completion
Defense Date: 8 August 2006
Approval Date: 29 September 2006
Submission Date: 27 September 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: ; apoptosis; cancer; EGF; EGF receptor; fibroblast; invasion; migration; prostate; STAT3
Other ID:, etd-09272006-164658
Date Deposited: 10 Nov 2011 20:02
Last Modified: 19 Dec 2016 14:37


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