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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-09272006-164658 |
| Date | 29 September 2006 |
| Creators | Zhou, Weixin |
| Contributors | Reza Zarnegar, Alan Wells, Thomas Smithgall, Jianhua Luo, Jennifer R Grandis |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-09272006-164658/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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