Activity of the suppressor of cytokine signaling-3 promoter in human non-small-cell lung cancer.
The Janus kinase (JAKs)/signal transducers and activators of transcription (STAT) signaling pathway is controlled by a classical feedback loop through suppressors of cytokine signaling (SOCS/JAB/SSI). Suppressors of cytokine signaling proteins are induced rapidly by activated STATs upon phosphorylation and act to block the cytokine signal. Abnormalities of the JAK/STAT pathway are associated with cancer. Recently, we cloned the functional 5' promoter region of the human SOCS-3 gene and showed that this region is highly conserved in murine and rat SOCS-3 promoters. In addition, we found that the wild type SOCS-3 promoter construct has significantly greater activity in human non-small-cell lung cancer (NSCLC) cell lines than in normal cells in accordance with STAT3 deregulation in these cells. Furthermore, we have confirmed that frequent hypermethylation of the functional SOCS-3 promoter correlates with its transcription silencing in NSCLC cell lines and primary lung cancer tissue samples. Restoration of SOCS-3 in lung cancer cells in which SOCS-3 has been methylation-silenced induces apoptosis and suppresses growth. Therefore, methylation silencing of SOCS-3 may be used as a marker for early detection of NSCLC. Suppressor of cytokine signaling-3 therapy may be useful for the treatment of lung cancer.
He
Biao
B
Comprehensive Cancer Center, University of California, San Francisco, USA.
You
Liang
L
Xu
Zhidong
Z
Mazieres
Julien
J
Lee
Amie Y
AY
Jablons
David M
DM
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000503:physiopathology*; D002455:Cell Division; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D053613:Janus Kinase 1; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; D053613:Janus Kinase 1