CXCR3 signaling in BRAFWT melanoma increases IL-8 expression and tumorigenicity

• Published in: PloS one 2015, Vol.10 (3), p.e0121140
• Main Authors: Jenkins, Molly H, Brinckerhoff, Constance E, Mullins, David W
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Carcinogenesis - metabolism; Cell growth; Cell Line, Tumor; Cell migration; Clinical trials; Cotton; Cotton, Norris; CXCR3 protein; Cytokines; Deprivation; Environmental stress; Fibroblasts; Humans; Hypoxia; Immunology; Interleukin 8; Interleukin-8 - genetics; Interleukin-8 - metabolism; Ligands; Lymph nodes; Male; Medical research; Medicine; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Molecular modelling; Mutation; Penicillin; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Receptors, CXCR3 - genetics; Receptors, CXCR3 - metabolism; Signal Transduction; Signaling; Survival; Tumorigenesis; Tumorigenicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0121140

Patients with early stage, radial growth phase (RGP) melanoma have a 97% survival rate; however, when the melanoma progresses to the invasive vertical growth phase (VGP), survival rates decrease to 15%. The targets of many clinical trials are the known genetic and molecular mechanisms involved in melanoma progression, with the most common oncogenic mutation being the BRAFV600E. However, less than half of melanomas harbor this mutation, and consequently, do not respond to the current BRAF targeted treatments. It is therefore critical to elucidate alternative mechanisms regulating melanoma progression. Increased expression of the chemokine receptor, CXCR3, on melanoma cells is correlated with increased metastasis and poor patient outcomes, suggesting a role for CXCR3 in the RGP to VGP transition. We found that endogenous CXCR3 can be induced in two RGP cell lines, BOWES (BRAFWT) and WM35 (BRAFV600E), with in vitro environmental stress and nutrient deprivation. Signaling via induced endogenous CXCR3 is linked with IL-8 expression in BOWES cells. Ectopic overexpression of CXCR3 in BOWES cells leads to increased ligand-mediated phERK, cellular migration, and IL-8 expression in vitro, and to increased tumorigenesis and lymph node metastasis in vivo. Our results demonstrate that, in BRAFWT melanomas, CXCR3 signaling mediates significant increases in IL-8 expression, suggesting that CXCR3 expression and signaling may represent a transformative event that drives the progression of BRAFWT melanomas. Expression of CXCR3 on BRAFWT melanoma cells may be a mediator of melanoma progression.