Transforming growth factor-β1, transforming growth factor-β2, and transforming growth factor-β3 enhance ovarian cancer metastatic potential by inducing a Smad3-dependent epithelial-to-mesenchymal transition

Thuy Vy Do, Lena A. Kubba, Hongyan Du, Charles D. Sturgis, Teresa K. Woodruff

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) is thought to play a role in the pathobiological progression of ovarian cancer because this peptide hormone is overexpressed in cancer tissue, plasma, and peritoneal fluid. In the current study, we investigated the role of the TGF-β/ Smad3 pathway in ovarian cancer metastasis by regulation of an epithelial-to-mesenchymal transition. When cancer cells were cultured on plastic, TGF-β1, TGF-β2, and TGF-β3 induced pro-matrix metalloproteinase (MMP) secretion, loss of cell-cell junctions, down-regulation of E-cadherin, up-regulation of N-cadherin, and acquisition of a fibroblastoid phenotype, consistent with an epithelial-tomesenchymal transition. Furthermore, Smad3 small interfering RNA transfection inhibited TGF-β-mediated changes to a fibroblastic morphology, but not MMP secretion. When cancer cells were cultured on a three-dimensional collagen matrix, TGF-β1, TGF-β2, and TGF-β3 stimulated both pro-MMP and active MMP secretion and invasion. Smad3 small interfering RNA transfection of cells cultured on a collagen matrix abrogated TGF-β-stimulated invasion and MMP secretion. Analysis of Smad3 nuclear expression in microarrays of serous benign tumors, borderline tumors, and cystadenocarcinoma revealed that Smad3 expression could be used to distinguish benign and borderline tumors from carcinoma (P = 0.006). Higher Smad3 expression also correlated with poor survival (P = 0.031). Furthermore, a direct relationship exists between Smad3 nuclear expression and expression of the mesenchymal marker N-cadherin in cancer patients (P = 0.0057). Collectively, these results implicate an important role for the TGF-β/Smad3 pathway in mediating ovarian oncogenesis by enhancing metastatic potential.

Original languageEnglish (US)
Pages (from-to)695-705
Number of pages11
JournalMolecular Cancer Research
Volume6
Issue number5
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Transforming growth factor-β1, transforming growth factor-β2, and transforming growth factor-β3 enhance ovarian cancer metastatic potential by inducing a Smad3-dependent epithelial-to-mesenchymal transition'. Together they form a unique fingerprint.

Cite this