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

Molly H Jenkins,Constance E Brinckerhoff,David W Mullins,Suzie Chen

doi:10.1371/journal.pone.0121140

Abstract

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. Implications: Expression of CXCR3 on BRAFWT melanoma cells may be a mediator of melanoma progression.

Highlights

Melanoma progression has been described as a multi-step process, with melanocytes changing to nevi, and primary melanoma with radial growth phase (RGP) transitioning to vertical growth phase (VGP) [1,2,3]
While endogenous CXCR3 can be induced with stress in WM35 cells, a human RGP BRAFV600E cell line, we found that IL-8 expression in these cells was not linked with CXCR3 signaling
We demonstrate that signaling through CXCR3 induces IL-8 expression in a Mitogen Activated Protein Kinase (MAPK)-dependent manner

Summary

Introduction

Melanoma progression has been described as a multi-step process, with melanocytes changing to nevi, and primary melanoma with radial growth phase (RGP) transitioning to vertical growth phase (VGP) [1,2,3]. CXCR3 Signaling Induces IL-8 in Melanoma unrelated to the current manuscript. These relationships do not alter the authors' adherence to all PLOS ONE policies on sharing data and materials, as detailed in the Journal’s guide for authors. The targets of many current clinical trials are known genetic and molecular mechanisms involved in melanoma progression, with the most common oncogenic mutation being the BRAFV600E (found in nearly 50% of melanoma) [9,10,11,12]. Since less than half of melanomas harbor the BRAFV600E mutation, and do not respond to the current targeted treatment, it is critical to delineate alternative mechanisms that regulate the progression of melanoma

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Results

Conclusion