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


METHODS
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-beta1, 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 Smad4-reduced 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.
Okano
Hirokazu
H
Department of General and Gastroenterological Surgery, Osaka Medical College, Osaka, Japan.
Shinohara
Hisashi
H
Miyamoto
Akiko
A
Takaori
Kyoichi
K
Tanigawa
Nobuhiko
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D020893:Receptor, ErbB-3 / Q000502:physiology*; D015398:Signal Transduction; D051901:Smad4 Protein; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D015534:Trans-Activators / Q000494:pharmacology*; D016212:Transforming Growth Factor beta; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020893:Receptor, ErbB-3