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.