While localized tumor growth may cause organ dysfunction and even death, metastases cause the vast majority (~90%) of human cancer deaths. Both autocrine and paracrine transforming growth factor-beta (TGF-beta) have been linked to invasive and metastatic tumor growth. The mechanism whereby autocrine TGF-beta elicits tumorigenic effects was investigated. The metastatic breast cancer cells, MDA-MB-231, secrete TGF-beta and express both the urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) that are important for cancer metastatic growth. Whether autocrine TGF-beta promotes invasive growth of MDA-MB-231 cells through regulation of uPA and/or MMP-9 protein levels and/or activity was studied. Inhibition of autocrine TGF-beta signaling decreased MDA-MB-231 cell invasion and uPA secretion. Inhibition of uPA proteolytic activity decreased cell invasion to the similar extent. The Smad proteins are the intracellular mediators for the canonical TGF-beta signaling pathway. However, TGF-beta receptors may transduce signals through Smad-independent pathways. My study demonstrates that the self-sufficiency of promoting invasive potential of tumor cells is through enhanced uPA secretion by autocrine TGF-beta in a Smad-dependent manner. While autocrine TGF-beta signaling modulates uPA protein secretion, exogenous TGF-beta increased uPA mRNA expression through RNA stabilization, suggesting distinct post-transcriptional mechanisms for regulation of uPA by different magnitudes of TGF-beta stimulation.
Smad4 is both a tumor promoter and a suppressor. We previously observed inverse protein expression of Smad4 and claudin-1 in intestinal epithelial and colorectal cancer (CRC) cells and tissues. Claudin-1 is a tight junction protein with potential of enhancing metastatic growth of CRC cells. Whether Smad4 may act as a tumor suppressor by inhibiting claudin-1 expression in CRC was studied. In the Smad4-deficient, claudin-1-positive HT29 and SW480 CRC cells, Smad4 expression specifically downregulated claudin-1 protein expression through possibly transcriptional suppression. Previous findings suggest TGF-beta signaling-independent functions of Smad4. My study demonstrates that the Smad4-mediated suppression of claudin-1 expression is independent of TGF-beta signaling in SW480 and HT29 cells. These findings suggest a novel mechanism underlying the Smad4 tumor suppressive function through regulation of a potential metastatic modulator, claudin-1, in a TGF-beta-independent manner in CRC cells.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04072006-133039 |
| Date | 14 April 2006 |
| Creators | Shiou, Sheng-Ru |
| Contributors | Professor R. Daniel Beauchamp |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-04072006-133039/ |
| 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 Vanderbilt University 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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