Activation of Stat3 in Human Melanoma Promotes Brain Metastasis
Published version of a preprint
Abstract
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…
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Constitutively active STAT3 contributes to the cancer phenotype by promoting motility and invasion, including in human melanoma where increased activation of STAT3 promotes metastasis to the brain.
“Constitutively active STAT3 further contributes to the cancer phenotype by promoting motility and invasion, including in human melanoma where increased activation of STAT3 promotes metastasis to the brain.82”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [82]
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“STAT3 in migration and invasion Constitutively active STAT3 further contributes to the cancer phenotype by promoting motility and invasion, including in human melanoma where increased activation of STAT3 promotes metastasis to the brain.(82) The metastatic action of STAT3 is, in part, mediated by matrix metalloprotein…”
- Authors
- Xie, T.-X., Huang, F.-J., Aldape, K. D., Kang, S.-H., Liu, M., Gershenwald, J. E., Xie, K., Sawaya, R., & Huang, S.
- Affiliations
- 1Neurosurgery, Departments of
- 2Pathology,
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Cancer Research
- Published
- 2006-03-15
- Volume
- 66
- Issue
- 6
- Pages
- 3188-3196
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2102978104
- Cited by
- 393
- References
- 1
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 3 · 2023: 15 · 2022: 8 · 2021: 15 · 2020: 20 · 2019: 27 · 2018: 23 · 2017: 25 · 2016: 30 · 2015: 19 · 2014: 24 · 2013: 34 · 2012: 31
- FWCI
- 17.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA-16672, P30CA016672)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- STAT3 activation, melanoma brain metastases, angiogenesis, tumor invasion, basic fibroblast growth factor, vascular endothelial growth factor, MMP-2, transcriptional regulation, dominant-negative STAT3
- MeSH terms
- Animals, Brain Neoplasms, Female, Humans, Melanoma, Mice, Inbred BALB C, Mice, Nude, Neoplasm Invasiveness, Neovascularization, Pathologic, Skin Neoplasms, Fibroblast Growth Factor 2, Matrix Metalloproteinase 2, Vascular Endothelial Growth Factor A, STAT3 Transcription Factor, Mice
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