Linked Life Data

19047140

Source:http://linkedlifedata.com/resource/pubmed/id/19047140

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2008-12-2
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1538-7445
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
68
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9634-42
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:19047140-Animals, pubmed-meshheading:19047140-Brain Neoplasms, pubmed-meshheading:19047140-Cell Line, Tumor, pubmed-meshheading:19047140-Female, pubmed-meshheading:19047140-Fibroblast Growth Factor 2, pubmed-meshheading:19047140-Humans, pubmed-meshheading:19047140-Janus Kinase 2, pubmed-meshheading:19047140-Melanoma, pubmed-meshheading:19047140-Mice, pubmed-meshheading:19047140-Mice, Inbred BALB C, pubmed-meshheading:19047140-Mice, Nude, pubmed-meshheading:19047140-Neoplasm Invasiveness, pubmed-meshheading:19047140-Neovascularization, Pathologic, pubmed-meshheading:19047140-STAT3 Transcription Factor, pubmed-meshheading:19047140-Signal Transduction, pubmed-meshheading:19047140-Suppressor of Cytokine Signaling Proteins, pubmed-meshheading:19047140-Transfection, pubmed-meshheading:19047140-Transplantation, Heterologous, pubmed-meshheading:19047140-Vascular Endothelial Growth Factor A
pubmed:year
2008
pubmed:articleTitle
Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis.
pubmed:affiliation
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural