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
Journal
Cancer Research
Journal Volume
67
Journal Issue
19
Pages
9066-9076
Date Issued
2007
Author(s)
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. ?2007 American Association for Cancer Research.
SDGs
Other Subjects
epidermal growth factor; epidermal growth factor receptor; Janus kinase; mitogen activated protein kinase; phosphatidylinositol 3 kinase; protein inhibitor; STAT3 protein; transcription factor Slug; transcription factor Snail; transcription factor Twist; uvomorulin; animal cell; article; breast carcinoma; cancer cell; cell structure; chromatin immunoprecipitation; controlled study; epithelium cell; gene activation; gene deletion; gene expression; gene expression regulation; gene mutation; human; human cell; human tissue; immunohistochemistry; mesenchyme cell; metastasis; nonhuman; null cell; priority journal; promoter region; protein expression; protein phosphorylation; protein protein interaction; signal transduction; spindle cell; tumor growth; Twist gene; upregulation; Animals; Base Sequence; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Dogs; Epidermal Growth Factor; Epithelial Cells; Gene Expression Regulation, Neoplastic; Humans; Mesoderm; Mice; Molecular Sequence Data; Promoter Regions (Genetics); Receptor, Epidermal Growth Factor; STAT3 Transcription Factor; Swiss 3T3 Cells; Twist Transcription Factor; Up-Regulation
Type
journal article