Hepatocyte growth factor (HGF), a cytokine of tumor microenvironment, exerts opposite effects on CXCR4 expression in MCF-7 (low invasive) and MDA-MB231 (highly invasive) breast carcinoma cells, and here, we show that completely different molecular mechanisms downstream of c-Src activation were involved. As experimental models, we used cells transfected with two CXCR4 promoter constructs and treated with HGF or cotransfected with c-Src wild-type (Srcwt) expression vector; phospho-c-Src formation was enhanced in both cell lines. In MCF-7 cells, consistent with activations of CXCR4Luc constructs after HGF treatment and Srcwt expression, Ets1 and nuclear factor-kappaB (NF-kappaB) transcription factors were activated. In contrast, in MDA-MB231 cells, CXCR4Luc construct, Ets1 and NF-kappaB activities decreased. The divergence point seemed to be downstream of HGF/c-Src and consisted in the interaction between c-Src and the substrate histone deacetylase 3 (HDAC3). Only in MDA-MB231 cells, HDAC3 level was enhanced in membranes and nuclei 30 min after HGF and colocalized/coimmunoprecipitated with phospho-c-Src and phosphotyrosine. Thus, the CXCR4 induction by HGF in MCF-7 cells required NF-kappaB and Ets1 activations, downstream of phosphoinositide-3-kinase/Akt, whereas in HGF-treated MDA-MB231 cells, HDAC3 activation via c-Src probably caused a reduction of transcription factor activities, such as that of NF-kappaB. These results indicate possible roles of HGF in invasive growth of breast carcinomas. By enhancing CXCR4 in low invasive tumor cells, HGF probably favors their homing to secondary sites, whereas by suppressing CXCR4 in highly invasive cells, HGF might participate to retain them in the metastatic sites.
|Titolo:||c-Src/histone deacetylase 3 interaction is crucial for hepatocyte growth factor dependent decrease of CXCR4 expression in highly invasive breast tumor cells|
|Autori interni:||DESIDERIO, MARIA ALFONSINA (Ultimo)|
MATTEUCCI, EMANUELA (Primo)
RIDOLFI, ELISA (Secondo)
BENDINELLI, PAOLA (Penultimo)
MARONI, PAOLA MARIA
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||ago-2007|
|Digital Object Identifier (DOI):||10.1158/1541-7786.MCR-07-0054|
|Appare nelle tipologie:||01 - Articolo su periodico|
File in questo prodotto:
- PubMed Central loading...