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Interleukin-6-induced Twist and N-cadherin enhance melanoma cell metastasis

Na, Yi-Ranga; Lee, Jin-Subb; Lee, Seok-Jongb; Seok, Seung-Hyeoka

doi: 10.1097/CMR.0000000000000021

Melanoma patients frequently have elevated serum levels of interleukin-6 (IL-6), which is correlated with a poor prognosis. IL-6 activates STAT3 phosphorylation, inducing the transcription of genes that regulate tumor cell proliferation and antiapoptosis. In addition, recent evidence suggests that IL-6 induces the epithelial-to-mesenchymal transition and enhances the invasiveness of tumor cells of epithelial origin. However, it is unknown whether IL-6 affects mesenchymal tumor cells. In this study, we examined the effects of IL-6 on melanoma cells and found that IL-6 can enhance their metastatic potential by regulating the expression of Twist and N-cadherin. First, we confirmed that human melanoma tissues express IL-6 (especially at the lesion site), the IL-6 receptor, N-cadherin, and nuclear Twist. Next, we found that IL-6 induces STAT3 phosphorylation in WM-266-4 human melanoma cells, resulting in transient upregulation of Twist, which is a key regulator of metastasis. Importantly, the expression of N-cadherin, a protein downstream of Twist, was also increased on the cell surface after treatment with IL-6. These cells showed enhanced invasiveness, assessed using an invasion assay, and formed more metastatic nodules in the lungs of NOD-SCID mice after an intravenous injection. Importantly, melanoma cells with knocked-down N-cadherin formed less lung nodules compared with control in the NOD-SCID mouse model. Our data suggest that increased serum IL-6 in cancer patients could increase the invasiveness of melanoma cells and accelerate metastasis. Blocking IL-6 in the melanoma microenvironment may therefore inhibit disease progression.

aDepartment of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul

bDepartment of Dermatology, Kyungpook National University School of Medicine, Daegu, Korea

Correspondence to Seung-Hyeok Seok, DVM, PhD, Department of Microbiology and Immunology, Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 110-799, Korea Tel: +82 2 740 8077; fax: +82 2 743 0881; e-mail:

Received March 23, 2013

Accepted August 20, 2013

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins