Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility

Rachel J. Paccione, Hiroshi Miyazaki, Vyomesh Patel, Ahmad Waseem, J. Silvio Gutkind, Zendra E. Zehner, William Andrew Yeudall

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

At later stages of tumor progression, epithelial carcinogenesis is associated with transition to a mesenchymal phenotype, which may contribute to the more aggressive properties of cancer cells and may be stimulated by growth factors such as epidermal growth factor and transforming growth factor-β. Previously, we found that cells derived from a nodal metastatic squamous cell carcinoma are highly proliferative and motile in vitro and tumorigenic in vivo. In the current study, we have investigated the role of vimentin in proliferation and motility. Cells derived from nodal metastasis express high levels of vimentin, which is undetectable in tumor cells derived from a synchronous primary lesion of tongue. Vimentin expression was enhanced by epidermal growth factor and transforming growth factor-β both independently and in combination. Use of RNA interference resulted in the generation of stable cell lines that express constitutively low levels of vimentin. RNA interference-mediated vimentin knockdown reduced cellular proliferation, migration, and invasion through a basement membrane substitute by 3-fold compared with nontargeting controls. In addition, cells with reduced vimentin reexpressed differentiation-specific keratins K13, K14, and K15 as a result of increased gene transcription as judged by quantitative PCR and promoter-reporter assays. Furthermore, cells in which vimentin expression was reduced showed a greatly decreased tumorigenic potential, as tumors developing from these cells were 70% smaller than those from control cells. The data suggest that reversal of the mesenchymal phenotype by inhibiting vimentin expression results in reexpression of epithelial characteristics and reduced tumor aggressiveness.

Original languageEnglish (US)
Pages (from-to)2894-2903
Number of pages10
JournalMolecular cancer therapeutics
Volume7
Issue number9
DOIs
StatePublished - Oct 22 2008
Externally publishedYes

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Vimentin
Keratins
RNA Interference
Down-Regulation
Growth
Neoplasms
Transforming Growth Factors
Epidermal Growth Factor
Phenotype
Tongue
Basement Membrane
Squamous Cell Carcinoma
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Cell Proliferation
Neoplasm Metastasis
Cell Line
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility. / Paccione, Rachel J.; Miyazaki, Hiroshi; Patel, Vyomesh; Waseem, Ahmad; Gutkind, J. Silvio; Zehner, Zendra E.; Yeudall, William Andrew.

In: Molecular cancer therapeutics, Vol. 7, No. 9, 22.10.2008, p. 2894-2903.

Research output: Contribution to journalArticle

Paccione, Rachel J. ; Miyazaki, Hiroshi ; Patel, Vyomesh ; Waseem, Ahmad ; Gutkind, J. Silvio ; Zehner, Zendra E. ; Yeudall, William Andrew. / Keratin down-regulation in vimentin-positive cancer cells is reversible by vimentin RNA interference, which inhibits growth and motility. In: Molecular cancer therapeutics. 2008 ; Vol. 7, No. 9. pp. 2894-2903.
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