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Preserved Smad4 Expression in the Transforming Growth Factor ß Signaling Pathway Is a Favorable Prognostic Factor in Patients with Advanced Gastric Cancer¹

First Department of Surgery, School of Medicine, Kagoshima University, Kagoshima 890-8520, Japan [C. X., S. N., S. T., S. H., S. I., G. T., M. B., T. A.], and Department of Surgery, Terada Hospital, Kagoshima 895-25, Japan [K. K.]

The signals of the transforming growth factor ß (TGF-ß) superfamily are conveyed through cell surface serine/threonine kinase receptors to the intracellular mediators known as Smads. Activation of Smads causes their translocation from the cytoplasm to the nucleus, where they function to control gene expression. The present study analyzed the expression of Smad4 and TGF-ß1 to determine their prognostic significance in advanced gastric cancer. Of 249 cases of advanced gastric cancer, 41 had invaded the muscular layer, 114 had invaded the subserosal layer, and 94 had invaded the serosa. Anti-Smad4 and TGF-ß1 antibodies were used for immunohistochemical staining. Reduced expression of Smad4 was 75.1%, whereas positive expression of TGF-ß1 was 39.6% in gastric cancer. Smad4 expression was related to the depth of tumor invasion (P < 0.05), and TGF-ß1 expression correlated with tumor gross type (P < 0.05). Postoperative survival analysis indicated that patients who had a tumor with reduced Smad4 expression had a poorer clinical outcome than those with preserved expression (P < 0.05). Furthermore, in patients with TGF-ß1-positive tumors, survival rate was significantly better in patients with preserved Smad4 expression than in those with reduced Smad4 expression (P < 0.05). According to multivariate analysis, Smad4 expression acted as an independent prognostic factor. Smad4 expression, particularly in the TGF-ß pathway, is an effective predictor of outcome for patients with advanced gastric cancer.

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