HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB.
CXCR4 is a chemokine receptor probably involved in the homing of metastatic breast cancer, and its expression is modulated by tumor environmental stimuli such as hepatocyte growth factor (HGF) and hypoxia. Here, we demonstrate that, depending on the stimulus, different transcription factors can cooperate in enhancing CXCR4 transcription in MCF-7 breast cancer cell line. In HGF-treated MCF-7 cells, the DNA binding of Ets1 activated by MAPK1/ERK1/2 transduction pathway as well as the DNA binding of NF-kappaB played a critical role in CXCR4 transcription and protein induction. Under HGF stimulation, the blockade of these transcription factors by dominant negatives and inhibitors prevented the expression of CXCR4 receptor, the activity of a gene reporter driven by CXCR4 promoter sequence and the chemoinvasion toward the CXCL12 ligand. NF-kappaB was activated also by hypoxia and contributed, with HIF-1, to the increase in CXCR4 expression. The results suggest that Ets1, specifically activated by HGF, might cooperate with NF-kappaB activity to enhance the invasive/metastatic phenotype of breast carcinoma cells.
Maroni
Paola
P
Institute of General Pathology, School of Medicine University of Milan, via Luigi Mangiagalli, 31-20133 Milan, Italy.
Bendinelli
Paola
P
Matteucci
Emanuela
E
Desiderio
Maria Alfonsina
MA
D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D017931:DNA Primers; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness; D050784:Proto-Oncogene Protein c-ets-1 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D017931:DNA Primers; C494041:ETS1 protein, human; D016328:NF-kappa B; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D017228:Hepatocyte Growth Factor