Purpose: The activation of signal transducer and activator of transduction (Stat) protein is thought to lead to the genesis of neoplasia by promoting cellular growth and preventing apoptosis. Similar to other Stats, Stat3 is activated by phosphorylation of a single tyrosine residue (Tyr705) by Janus kinase in response to cytokine stimulation, and dimerizes via a reciprocal -SH2 phospho-tyrosine interaction. The dimeric Stat3 translocates to the nucleus, where it binds to defined DNA elements within the promoter region of target genes and activates their transcription. However, there are few reports on the role of Stat3 signaling in gastric cancer. Its relationship to gastric cancer and patient survival has not been determined in a large retrospective study. Recently, an antibody specific for the activated (phospho-Tyr705) form of Stat3 has become available. To further elucidate the role of Stat3 in gastric cancers, the expression patterns of Phospho-tyrosine residue 705 (Tyr705) Stat3 were correlated with survival outcome and clinicopathological parameters in a large cohort of Japanese gastric cancers. Experimental Design: Immunohistochemical analysis of Phospho-Stat3 was performed on 110 gsatric cancer specimens, 10 gastric adenomas and 10 normal gastric mucosa (gastric tumor free). These results were correlated with overall survival and other clinicopathological data. Results: Positive Phospho-Stat3 (Tyr705) cytoplasmic expression was seen in 47 (43%) gastric cancers (in 44% well differentiated, 53% moderately differentiated and 40% poorly differentiated respectively)and 10% of adenomas but not in normal gastric mucosa. Neither cytoplasmic expression showed significant association with survival or other clinical parameters. Upon analysis of positive Phospho-Stat3 (Tyr705) nuclear expression, seen in 25 (23%) cancers (in 12.5% well differentiated, 21.4% moderately differentiated and 27.4% poorly differentiated respectively) but not in adenomas and normal mucosa. Nuclear expression was not showed significant association with other clinical parameters. However, nuclear positive tumors had a significantly improved survival at short-term 5-year survival analysis (P < 0.05). Conclusions: These findings support a role for Phospho-Stat3 (Tyr705) overexpression in gastric carcinogenesis and also provide initial evidence that Phospho-Stat3 (Tyr705) nuclear expression may be a marker for improved survival independent of other prognostic markers.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]