The
chemokine receptor CXCR4 and its
ligand CXCL12 have been shown to mediate the
metastasis of many malignant
tumors including
breast carcinoma. Interaction between
hepatocyte growth factor (HGF) and the
Met receptor tyrosine kinase mediates development and progression of
cancers. HGF is able to induce CXCR4 expression and contributes to
tumor cell invasiveness in
breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of
breast cancer cells is still unclear. In this study, we found that HGF induced functional
CXCR4 receptor expression in
breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-
siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in
breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via
phosphoinositide (PI) 3-kinases. HGF treatment also increased
MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and
phosphatidylinositol 3-kinase may attenuate
MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and
metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve
PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and
metastasis of
breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate
cancer cell spreading.