dc.creator | Shiou, Sheng-Ru | |
dc.date.accessioned | 2020-08-22T00:26:59Z | |
dc.date.available | 2007-04-14 | |
dc.date.issued | 2006-04-14 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-04072006-133039 | |
dc.identifier.uri | http://hdl.handle.net/1803/12039 | |
dc.description.abstract | 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. | |
dc.format.mimetype | application/pdf | |
dc.subject | Transforming growth factors-beta -- Receptors | |
dc.subject | Transforming growth factors-beta -- Physiological effect | |
dc.subject | Smad4 | |
dc.subject | uPA | |
dc.subject | claudin-1 | |
dc.subject | BMP | |
dc.subject | TGF-beta | |
dc.subject | Cancer invasiveness | |
dc.subject | Metastasis -- Molecular aspects | |
dc.title | Transforming Growth Factor-beta and Smad4 Regulation of Invasive and Metastatic Behavior in Cancer Cells | |
dc.type | dissertation | |
dc.contributor.committeeMember | Professor R. Daniel Beauchamp | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Cell and Developmental Biology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2007-04-14 | |
local.embargo.lift | 2007-04-14 | |