epidermal-growth-factor and Chromosomal-Instability

Most sporadic carcinomas with high metastatic activity show an increased rate of changes in chromosome structure and number, known as chromosomal instability (CIN). However, the role of CIN in driving invasiveness remains unclear. Using an epithelial model in Drosophila, we present evidence that CIN promotes a rapid and general invasive behavior. Cells with an abnormal number of chromosomes delaminate from the epithelium, extend actin-based cellular protrusions, form membrane blebs, and invade neighboring tissues. This behavior is governed by the activation of non-muscle Myosin II by Rho kinase and by the expression of the secreted EGF/Spitz ligand. We unravel fundamental roles of the mitogen-activated protein kinase pathways mediated by the Fos proto-oncogene and the Capicua tumor suppressor gene in the invasive behavior of CIN-induced aneuploid cells. Our results support the proposal that the simple production of unbalanced karyotypes contributes to CIN-induced metastatic progression.

Topics: Aneuploidy; Animals; Apoptosis; Blister; Carcinoma; Chromosomal Instability; Drosophila melanogaster; Drosophila Proteins; Epidermal Growth Factor; Epithelium; ErbB Receptors; HMGB Proteins; Membrane Proteins; Mitogen-Activated Protein Kinases; Myosin Type II; Neoplasm Invasiveness; Proto-Oncogene Proteins c-fos; Repressor Proteins; rho-Associated Kinases

Loss of the maintenance of genetic material is a critical step leading to tumorigenesis. It was reported that overexpression of Aurora-A and the constitutive activation of the epidermal growth factor (EGF) receptor (EGFR) are implicated in chromosome instability. In this study, we examined that when cells treated with EGF result in centrosome amplification and microtubule disorder, which are critical for genetic instability. Interestingly, the expression of Aurora-A was also increased by EGF stimulus. An immunofluorescence assay indicated that EGF can induce the nuclear translocation of EGFR. Chromatin immunoprecipitation (ChIP) and re-ChIP assays showed significant EGF-induced recruitment of nuclear EGFR and signal transducer and activator of transcription 5 (STAT5) to the Aurora-A promoter. A co-immunoprecipitation assay further demonstrated that EGF induces nuclear interaction between EGFR and STAT5. A small interfering (si)RNA knockdown assay also showed that EGFR and STAT5 are indeed involved in EGF-increased Aurora-A gene expression. Altogether, this study proposes that the nuclear EGFR associates with STAT5 to bind and increase Aurora-A gene expression, which ultimately may lead to chromosome instability and tumorigenesis. The results also provide a novel linkage between the EGFR signaling pathway and overexpression of Aurora-A in tumorigenesis and chromosome instability.

Topics: Active Transport, Cell Nucleus; Animals; Aurora Kinases; Cell Line; Cell Nucleus; Centrosome; Chromosomal Instability; Cricetinae; Epidermal Growth Factor; ErbB Receptors; Humans; Microtubules; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Receptors, Cytoplasmic and Nuclear; STAT5 Transcription Factor; Transcriptional Activation