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Activation of Stat3 in Human Melanoma Promotes Brain Metastasis

Departments of ¹ Neurosurgery, ² Pathology, ³ Surgical Oncology, ⁴ Gastrointestinal Medical Oncology, and ⁵ Cancer Biology, The University of Texas M.D. Anderson Cancer Center and ⁶ Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Suyun Huang, Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Unit 1004, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-834-6232; Fax: 713-834-6257; E-mail: suhuang{at}mail.mdanderson.org.

Brain metastasis is a major cause of morbidity and mortality in patients with melanoma. The molecular changes that lead to brain metastasis remain poorly understood. In this study, we developed a model to study human melanoma brain metastasis and found that Stat3 activity was increased in human brain metastatic melanoma cells when compared with that in cutaneous melanoma cells. The expression of activated Stat3 is also increased in human brain metastasis specimens when compared with that in the primary melanoma specimens. Increased Stat3 activation by transfection with a constitutively activated Stat3 enhanced brain metastasis, whereas blockade of Stat3 activation by transfection with a dominant-negative Stat3 suppressed brain metastasis of human melanoma cells in animal models. Furthermore, altered Stat3 activity profoundly affected melanoma angiogenesis in vivo and melanoma cell invasion in vitro and significantly affected the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2) in vivo and in vitro. Finally, Stat3 activity transcriptionally regulated the promoter activity of bFGF in addition to VEGF and MMP-2 in human melanoma cells. These results indicated that Stat3 activation plays an important role in dysregulated expression of bFGF, VEGF, and MMP-2 as well as angiogenesis and invasion of melanoma cells and contributes to brain metastasis of melanoma. Therefore, Stat3 activation might be a new potential target for therapy of human melanoma brain metastases. (Cancer Res 2006; 66(6): 3188-96)

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