Concomitant Overexpression of Cyclooxygenase-2 in HER-2–Positive on Smad4-Reduced Human Gastric Carcinomas Is Associated with a Poor Patient Outcome

Abstract

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)-␤, 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-␤1, and Smad4, an intracellular mediator that transmits the TGF-␤ 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-␤1 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 Smad4-reduced tumors.Conclusions: These results support the possibility that signal transduction via HER-2 and the TGF-␤/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-␤-initiated overexpression of COX-2, which is associated with a poor prognosis for patients with gastric cancer.

Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR

“…A number of studies have previously shown COX-2 expression to correlate with clinicopathologic variables in gastric cancer, such as depth of tumor invasion, size, lymph node metastasis, stage, and microvessel density (26 -37), but the association of COX-2 with survival has been controversial. Several groups have reported no correlation with survival (30, 32, 38, 39) whereas others have described COX-2 to correlate with survival, but in a nonindependent manner (28,37) or in patients with an advanced disease (36). However, Shi et al (35) have reported that COX-2 is an independent prognostic factor in gastric cancer.…”

Impaired transforming growth factor signalling in Barrett's carcinogenesis due to frequent SMAD4 inactivation

“…Functional complementation of impaired TGF-b signalling occurred in BIC-1 cells when Smad4 expression was re-established ( fig 9). smad4 was first identified as a candidate tumour suppressor in pancreatic cancer, 8 and since then mutations have been detected in one third of metastatic colorectal cancers, 9 27 two thirds of gastric carcinomas, 28 and recently a complex pattern of mutations and abnormal splicing of Smad4 has been demonstrated in thyroid tumours. 29 Furthermore, mice heterozygous for smad4 develop gastric polyps months after birth that progress to invasive carcinoma.…”

Cyclooxygenase-2 and Gastric Cancer

“…In gastric cancer we and others have shown that COX-2 expression is associated with intestinal histological subtype, proximal location, large tumor size, and advanced stage [27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Association of COX-2 with survival has been controversial, since some studies show no such link [32][33][34].…”