Trial Information

Association and Mechanism Between Cyclooxygenase-2 and Interleukin-6 in Gastric Cancer

Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis
through multiple mechanisms in a number of malignancies, including gastric carcinoma (GC).
Cyclooxygenase-2 (COX-2), an inducible enzyme pivotal in the inflammatory response, converts
arachidonic acid to the prostaglandins (PGs) required in initiating and maintaining
reactions during the inflammatory process. Over-expression of COX-2 has been reported in a
wide variety of cancers and is therefore implicated to play an important role in
carcinogenesis. COX-2 can be blocked by non-steroidal anti-inflammatory drugs (NSIADs) and
is currently the most studied therapeutic target of NSAIDs. Clinically, NSAIDs have long
been used to treat various inflammatory or rheumatologic disorders.

Earlier clinical studies have confirmed an association between COX-2 over-expression and GC
occurrence. The known mechanisms by which COX-2 promotes carcinogenesis include evasion from
apoptosis, suppression of immunity, promotion of angiogenesis, and facilitation of
invasiveness. However, inflammation-associated factors mediating the effects of COX-2 on
carcinogenesis remain largely unknown. Interleukin-6 (IL-6) is a pro-inflammatory cytokine
associated with gastritis and GC. Our earlier works has disclosed that IL-6 can promote
angiogenic and anti-apoptotic ability of GC. However, the relationship between COX-2 and
IL-6 in GC remains unknown.

The present study aims to investigate the clinical association between COX-2 and IL-6 in GC,
to use a GC cell model for experimental study on causation and mechanism, and to verify the
in vivo effect of COX-2 on IL-6 by an animal model.

We will collect 100 consecutive surgical samples of GC from the pathology archive of
National Taiwan University Hospital and use immunohistochemical stain to compare protein
expression in GC. The clinical study is to define certain subgroups of GC exhibiting an
association between COX-2 and IL-6. In experimental study, we will clarify the causal
relationship by the dose- and time-dependent experiments of COX-2 transient transfection in
a GC cell line. COX-2 acts mainly via PGs, like PGE2. Therefore, we also stimulate GC cells
with exogenous stimulation of PGE2 and EP receptor 1-4 agonists to determine the possible
way(s) by which COX-2 induces IL-6 expression. A selective COX-2 inhibitor NS-398 and
various inhibitors of PGE2 receptors are used as well to block COX-2 for determining the
signaling pathway of COX-2 on IL-6. Finally, we will establish a stable COX-2
over-expressing transfectant of GC cells and its control vector transfectant for xenograft
implantation study on mice. A COX-2 selective agent, celecoxib, will be administered orally
to mice and tumor blocks will be harvested for determination of IL-6 expression.

The present study will provide clearer understanding of the role of COX-2 on the
pro-inflammatory cytokine IL-6 in GC in both clinical and basic aspects. It might also stand
for a model capable of systemically investigating the role of COX-2 on various cytokines
implicated in GC.