CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion.
The aggressiveness of malignant melanoma is associated with differential expression of CXCL-8 and its receptors, CXCR1 and CXCR2. However, the precise functional role of these receptors in melanoma progression remains unclear. In this study, we investigate the precise functional role of CXCR1 and CXCR2 in melanoma progression. CXCR1 or CXCR2 were stably overexpressed in human melanoma cell lines, SBC-2 (non-tumourigenic) and A375P (low-tumourigenic) exhibiting low endogenous expression of receptors. Functional assays were performed to study the resulting changes in cell proliferation, motility and invasion, and in vivo tumour growth using a mouse xenograft model. Our data demonstrated that CXCR1- or CXCR2-overexpressing SBC-2 and A375P melanoma cells had enhanced proliferation, chemotaxis and invasiveness in vitro. Interestingly, CXCR1 or CXCR2 overexpression in SBC-2 cells induced tumourigenicity, and A375P cells significantly enhanced tumour growth as examined in vivo. Immunohistochemical analyses showed significantly increased tumour cell proliferation and microvessel density and reduced apoptosis in tumours generated from CXCR1- or CXCR2-overexpressing melanoma cells. CXCR1- or CXCR2-induced modulation of melanoma cell proliferation and migration was observed to be mediated through the activation of ERK1/2 phosphorylation. Together, these studies demonstrate that CXCR1 and CXCR2 play essential role in growth, survival, motility and invasion of human melanoma.
Singh
S
S
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5845, USA.
Nannuru
K C
KC
Sadanandam
A
A
Varney
M L
ML
Singh
R K
RK
D017209:Apoptosis / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000502:physiology; D009361:Neoplasm Invasiveness; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000502:physiology*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3