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CD82/KAI expression prevents IL-8-mediated endothelial gap formation in late-stage melanomas

Oncogene volume 33, pages 2898–2908 (2014)Cite this article

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Abstract

Melanoma cells facilitate endothelial gap formation, the first step during tumor transendothelial migration, which is mediated by both adhesion and endogenously produced chemokines (in particular, interleukin-8 (IL-8)). Tetraspanins are localized to the cell surface in cancer and participate in various functions including invasion of tissues mediated by secretion of cytokines and matrix metalloproteinases. However, little is known about the role of CD82 tetraspanins in malignant melanomas during cancer cell invasion. In this study, we investigated the functional importance of CD82 expression in melanoma-mediated gap formation by using cDNAs to induce CD82 expression in highly invasive melanoma cell lines. Results showed that CD82 expression inhibited melanoma cell-induced gap formation, melanoma cell extravasation in vitro and subsequent lung metastasis development in vivo. Mechanistic studies showed that inducible expression of CD82 in highly metastatic melanoma cells significantly increased p21 expression upon binding of Duffy antigen receptor group (DARC), inducing tumor cell senescence and interrupting IL-8-mediated vascular endothelial (VE)-cadherin disassembly. Taken together, these studies provide a rationale for using drug therapies that restore CD82 expression and inhibit IL-8 production to inhibit late-stage melanoma cell extravasation and subsequent metastasis development.

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Acknowledgements

We acknowledge Chris Goodrich who kindly provided technical support. We also acknowledge Dr Meenhard Herlyn for kindly providing WM35 and WM793 cells. We thank Dr Justin Brown for letting us use his Odyssey system to develop the western blots. This work was supported by NIH Grant CA-127892-01A1, American Cancer Society Grant RSG-04-053-01-GMC and The Foreman Foundation for Melanoma Research (GPR); NIH Grants CA-125707 (CD); and Johnson & Johnson Innovative Technology Research Seed Grant Program (CD and GPR).

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  1. Professor GP Robertson, Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. E-mail: gprobertson@psu.edu

Authors and Affiliations

  1. Department of Bioengineering, The Pennsylvania State University, University Park, PA, USA

    P Khanna & C Dong

  2. Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    C-Y Chung, R I Neves & G P Robertson

  3. Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    R I Neves & G P Robertson

  4. Penn State Melanoma Therapeutic Program, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    R I Neves & G P Robertson

  5. Cutaneous Oncology Program, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    R I Neves

  6. Department of Surgery, Division of Plastic Surgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    R I Neves

  7. Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    G P Robertson

  8. Pennsylvania State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    G P Robertson & C Dong

  9. The Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA, USA

    G P Robertson

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Correspondence to G P Robertson or C Dong.

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Khanna, P., Chung, CY., Neves, R. et al. CD82/KAI expression prevents IL-8-mediated endothelial gap formation in late-stage melanomas. Oncogene 33, 2898–2908 (2014). https://doi.org/10.1038/onc.2013.249

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