Skip to main content

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.

Publication ,  Journal Article
Lo, H-W; Hsu, S-C; Xia, W; Cao, X; Shih, J-Y; Wei, Y; Abbruzzese, JL; Hortobagyi, GN; Hung, M-C
Published in: Cancer Res
October 1, 2007

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

October 1, 2007

Volume

67

Issue

19

Start / End Page

9066 / 9076

Location

United States

Related Subject Headings

  • Up-Regulation
  • Twist-Related Protein 1
  • Swiss 3T3 Cells
  • STAT3 Transcription Factor
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Molecular Sequence Data
  • Mice
  • Mesoderm
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lo, H.-W., Hsu, S.-C., Xia, W., Cao, X., Shih, J.-Y., Wei, Y., … Hung, M.-C. (2007). 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. Cancer Res, 67(19), 9066–9076. https://doi.org/10.1158/0008-5472.CAN-07-0575
Lo, Hui-Wen, Sheng-Chieh Hsu, Weiya Xia, Xinyu Cao, Jin-Yuan Shih, Yongkun Wei, James L. Abbruzzese, Gabriel N. Hortobagyi, and Mien-Chie Hung. “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.Cancer Res 67, no. 19 (October 1, 2007): 9066–76. https://doi.org/10.1158/0008-5472.CAN-07-0575.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

October 1, 2007

Volume

67

Issue

19

Start / End Page

9066 / 9076

Location

United States

Related Subject Headings

  • Up-Regulation
  • Twist-Related Protein 1
  • Swiss 3T3 Cells
  • STAT3 Transcription Factor
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Molecular Sequence Data
  • Mice
  • Mesoderm
  • Humans