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Title page for ETD etd-04072006-133039

Type of Document Dissertation
Author Shiou, Sheng-Ru
Author's Email Address sr.shiou@vanderbilt.edu
URN etd-04072006-133039
Title Transforming Growth Factor-beta and Smad4 Regulation of Invasive and Metastatic Behavior in Cancer Cells
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Professor R. Daniel Beauchamp Committee Member
  • Transforming growth factors-beta -- Receptors
  • Transforming growth factors-beta -- Physiological effect
  • Smad4
  • uPA
  • claudin-1
  • BMP
  • TGF-beta
  • Cancer invasiveness
  • Metastasis -- Molecular aspects
Date of Defense 2005-12-13
Availability unrestricted
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.

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