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Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis.

Abstract
Our recent study found that activation of signal transducer and activator of transcription 3 (Stat3) is up-regulated in human brain metastatic cells and contributes to brain metastasis of melanoma. However, the molecular mechanisms underlying this increased Stat3 activation and effect on brain metastasis are unknown. In this report, we showed that the expression of Janus-activated kinase 2 (JAK2), a Stat3 activator, was increased, whereas the expression of a negative regulator of Stat3, suppressor of cytokine signaling-1 (SOCS-1), was reduced in the brain metastatic melanoma cell line A375Br, relative to that in the parental A375P cell line. Consistently, SOCS-1 expression was also lower in the human brain metastatic tissues than in the primary melanoma tissues. Mechanistically, increased JAK2 expression in the A375Br cells was due to, at least in part, its decreased degradation, which was directly correlated with low expression of SOCS-1. Moreover, restoration of SOCS-1 expression resulted in the inhibition of Stat3 activation, whereas depletion of SOCS-1 up-regulated Stat3 activation. These clinical, experimental, and mechanistic findings strongly suggest that increased activation of Stat3 in brain metastatic melanoma cells might be due to decreased SOCS-1 expression. Furthermore, restoration of SOCS-1 expression in brain metastatic A375Br cells significantly inhibited brain metastasis in animal models (P<0.001). Additionally, alterations of SOCS-1 expression profoundly affected the expression of matrix metalloproteinase-2 (MMP-2), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) and the melanoma cell invasion and angiogenesis. Collectively, these data suggest that the loss of SOCS-1 expression is a critical event, leading to elevated Stat3 signaling and overexpression of MMP-2, bFGF, and VEGF, as well as enhanced invasion and angiogenesis of melanoma cells, consequently promoting brain metastasis.
AuthorsFeng-Ju Huang, Patricia S Steeg, Janet E Price, Wen-Tai Chiu, Ping-Chieh Chou, Keping Xie, Raymond Sawaya, Suyun Huang
JournalCancer research (Cancer Res) Vol. 68 Issue 23 Pg. 9634-42 (Dec 01 2008) ISSN: 1538-7445 [Electronic] United States
PMID19047140 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • JAK2 protein, human
  • Janus Kinase 2
Topics
  • Animals
  • Brain Neoplasms (blood supply, genetics, metabolism, secondary)
  • Cell Line, Tumor
  • Female
  • Fibroblast Growth Factor 2 (biosynthesis, genetics)
  • Humans
  • Janus Kinase 2 (biosynthesis, genetics)
  • Melanoma (blood supply, genetics, metabolism, secondary)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic (metabolism, pathology)
  • STAT3 Transcription Factor (metabolism)
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins (biosynthesis, genetics)
  • Transfection
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A (biosynthesis)

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