Concomitant overexpression of cyclooxygenase-2 in HER-2-positive on Smad4-reduced human gastric carcinomas is associated with a poor patient outcome

Purpose: The expression of cyclooxygenase-2 (COX-2) is known to be involved in gastric carcinogenesis and tumor progression, but little is known about the mechanisms responsible for the up-regulation of COX-2. We examined the involvement of two growth factor-signaling systems, HER-2 and transforming growth factor (TGF)-beta, in the induction of COX-2 in human gastric cancer tissue. Experimental Design: COX-2 expression was detected by immunohistochemistry in surgical specimens obtained from 166 patients with advanced gastric cancer; possible correlations between the expression of COX-2 and the expression of HER-2, TGF-betal, and Smad4, an intracellular mediator that transmits the TGF-beta signal, were then analyzed. Results: COX-2 protein was overexpressed in 91 (54.8%) tumors; COX-2 overexpression was correlated with a differentiated histologic type, deep invasion, and positive lymph node metastasis. COX-2 was frequently overexpressed in HER-2-positive tumors (19 of 22, 86.4%) and in Smad4-reduced tumors (67 of 104, 64.4%) but irrelevant to the TGF-beta1 expression status. The expression levels of COX-2 and HER-2 and the reduction in Smad4 were all associated with a poor patient outcome. A multivariate analysis demonstrated a significantly poor outcome for the concomitant overexpression of COX-2 in patients with Smad4reduced tumors. Conclusions: These results support the possibility that signal transduction via HER-2 and the TGF-beta/Smad system may be implicated in COX-2 expression and that the reduction of Smad4 may be, in part, of causal significance in the TGF-beta-initiated overexpression of COX-2, which is associated with a poor prognosis for patients with gastric cancer.