A Novel Activating Function of C-src and Stat3 on Hgf Transcription in Mammary Carcinoma Cells.
From: Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Queen’s University Cancer Research Institute, Kingston, ON, Canada.
Oncogene
- Publish Date: May 2006
- ISSN: 0950-9232
- Volume: 25
- Issue: 19
- Pages: 2773-84
- Medium: Print
- Language: English
- Citation (JAMA): Wojcik E J, Sharifpoor S, Miller N A, et al. A Novel Activating Function of C-src and Stat3 on Hgf Transcription in Mammary Carcinoma Cells.. Oncogene May 2006;25:2773-84
Abstract
In the normal breast, hepatocyte growth factor (HGF) is primarily expressed by stromal cells, and stimulates in a paracrine manner epithelial cells expressing the HGF receptor (Met). In invasive human breast carcinomas, HGF and Met are frequently overexpressed, possibly establishing an autocrine HGF/Met loop that promotes tumour cell invasion. However, the mechanisms leading to autocrine HGF expression in carcinoma cells are not known. We previously demonstrated a cooperative effect between c-Src and Stat3 in the activation of HGF transcription in mammary carcinoma cells. The present report defines a novel Stat3 consensus site at nt -95 in the HGF promoter that is highly conserved in human and mouse, and is required for c-Src and Stat3 to activate HGF transcription in breast epithelial cells. DNA-protein binding studies demonstrated high affinity binding of a Stat3-containing complex to the nt -95 site. Endogenous Stat3 binding to this region of the HGF promoter in carcinoma cells expressing HGF was demonstrated using a chromatin immunoprecipitation assay. In addition, coexpression of Stat3 and activated c-Src caused increased expression of endogenous HGF mRNA and protein and marked cell scattering in breast epithelial cells. Our results delineate a novel c-Src/Stat3-dependent mechanism that regulates HGF promoter activity, and is linked to transformation of mammary epithelial cells.
Mesh Headings (Keywords): Animals, Chromatin Immunoprecipitation, Electrophoretic Mobility Shift Assay, Female, Gene Expression Regulation, Neoplastic, Genes, Dominant, Hepatocyte Growth Factor, Luciferases, Mammary Neoplasms, Experimental, Mice, Mutation, Proto-Oncogene Proteins pp60(c-src), RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, Trans-Activation (Genetics), Transcription, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 16407846
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