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Molecular Biology, Pathobiology, and Genetics

Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression

Hui-Wen Lo, Sheng-Chieh Hsu, Weiya Xia, Xinyu Cao, Jin-Yuan Shih, Yongkun Wei, James L. Abbruzzese, Gabriel N. Hortobagyi and Mien-Chie Hung
Hui-Wen Lo
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Sheng-Chieh Hsu
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Weiya Xia
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Xinyu Cao
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Jin-Yuan Shih
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Yongkun Wei
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James L. Abbruzzese
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Gabriel N. Hortobagyi
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Mien-Chie Hung
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DOI: 10.1158/0008-5472.CAN-07-0575 Published October 2007
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Abstract

Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression. [Cancer Res 2007;67(19):9066–76]

  • EGFR
  • STAT3
  • TWIST
  • EMT
  • Cellular, molecular, and tumor biology
  • Signal transduction
  • Metastasis/metastasis genes/metastasis models

Footnotes

  • Note: Current address for H-W. Lo: Department of Surgery (Box 3156), Duke University School of Medicine, 103 Research Drive, Durham, NC 27710.

  • Received February 12, 2007.
  • Revision received June 12, 2007.
  • Accepted July 25, 2007.
  • ©2007 American Association for Cancer Research.
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Cancer Research: 67 (19)
October 2007
Volume 67, Issue 19
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Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression
Hui-Wen Lo, Sheng-Chieh Hsu, Weiya Xia, Xinyu Cao, Jin-Yuan Shih, Yongkun Wei, James L. Abbruzzese, Gabriel N. Hortobagyi and Mien-Chie Hung
Cancer Res October 1 2007 (67) (19) 9066-9076; DOI: 10.1158/0008-5472.CAN-07-0575

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Epidermal Growth Factor Receptor Cooperates with Signal Transducer and Activator of Transcription 3 to Induce Epithelial-Mesenchymal Transition in Cancer Cells via Up-regulation of TWIST Gene Expression
Hui-Wen Lo, Sheng-Chieh Hsu, Weiya Xia, Xinyu Cao, Jin-Yuan Shih, Yongkun Wei, James L. Abbruzzese, Gabriel N. Hortobagyi and Mien-Chie Hung
Cancer Res October 1 2007 (67) (19) 9066-9076; DOI: 10.1158/0008-5472.CAN-07-0575
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