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

Feng Ju Huang, Patricia S. Steeg, Janet E. Price, Wen Tai Chiu, Ping Chieh Chou, Keping Xie, Raymond Sawaya, Suyun Huang

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9634-9642
Number of pages9
JournalCancer Research
Volume68
Issue number23
DOIs
Publication statusPublished - 2008 Dec 1

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STAT3 Transcription Factor
Melanoma
Cytokines
Neoplasm Metastasis
Brain
Janus Kinase 2
Transcriptional Activation
Matrix Metalloproteinase 2
Fibroblast Growth Factor 2
Vascular Endothelial Growth Factor A
Cell Line
Animal Models

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Huang, Feng Ju ; Steeg, Patricia S. ; Price, Janet E. ; Chiu, Wen Tai ; Chou, Ping Chieh ; Xie, Keping ; Sawaya, Raymond ; Huang, Suyun. / Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis. In: Cancer Research. 2008 ; Vol. 68, No. 23. pp. 9634-9642.
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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.",
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Huang, FJ, Steeg, PS, Price, JE, Chiu, WT, Chou, PC, Xie, K, Sawaya, R & Huang, S 2008, 'Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis', Cancer Research, vol. 68, no. 23, pp. 9634-9642. https://doi.org/10.1158/0008-5472.CAN-08-1429

Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis. / Huang, Feng Ju; Steeg, Patricia S.; Price, Janet E.; Chiu, Wen Tai; Chou, Ping Chieh; Xie, Keping; Sawaya, Raymond; Huang, Suyun.

In: Cancer Research, Vol. 68, No. 23, 01.12.2008, p. 9634-9642.

Research output: Contribution to journalArticle

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T1 - Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis

AU - Huang, Feng Ju

AU - Steeg, Patricia S.

AU - Price, Janet E.

AU - Chiu, Wen Tai

AU - Chou, Ping Chieh

AU - Xie, Keping

AU - Sawaya, Raymond

AU - Huang, Suyun

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AB - 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.

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