Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus.

PURPOSE The members of the Smad family play key rolesin regulating gene expression in the transforming growth factor (TGF)-beta1 signaling pathways. Activation of Smads causes their translocation from the cytoplasm to the nucleus, where they function as transcription factors. The present study analyzed the expression and clinicopathological significance of Smad4 and TGF-beta1 in squamous cell carcinoma of the esophagus. EXPERIMENTAL DESIGN Immunohistochemistry was used to investigate the expression of Smad4 and TGF-beta1 proteins in 258 patients with squamous cell carcinoma of the esophagus. The relationship between expression of these proteins and clinicopathological factors was analyzed, and the usefulness of Smad4 in disease prognosis was evaluated in relation to TGF-beta1 expression. RESULTS Smad4 expression was preserved in 32.2% of tumors, and TGF-beta1 expression was identified in 42.6% of tumors. Patients with preserved expression of Smad4 had a higher rate of early-stage carcinoma (P < 0.01) and fewer lymph node metastases (P < 0.01) than those with reduced Smad4 expression. The expression of TGF-beta1 was not associated with any of the clinicopathological factors. Postoperative survival analysis indicated that patients with a tumor in which Smad4 expression was reduced had worse clinical outcomes than those with preserved expression (P = 0.01). In patients with TGF-beta1-negative tumors, the survival rate was significantly higher in patients with a preserved level of Smad4 expression than in those with reduced Smad4 expression (P = 0.02). However, according to multivariate analysis, Smad4 expression could not be used as an independent prognostic factor. CONCLUSIONS Although Smad4 expression could not be used as a prognostic factor, its expression reflected tumor progression such as tumor depth and lymph node metastasis.