The effects of cyclooxygenase2-prostaglandinE2 pathway on Helicobacter pylori-induced urokinase-type plasminogen activator system in the gastric cancer cells.
BACKGROUND
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in the destruction of the extracellular matrix and basement membrane. The induction of uPA and uPAR in the gastric cancer cells with H. pylori has been demonstrated previously. The involvement of COX-2-PGE2 pathway in the uPA system (uPA and uPAR) expression is unclear.


METHODS
Gastric cancer cells (MKN45) were co-cultured with H. pylori standard strain (NCTC11637). The specific inductions of uPA and uPAR mRNA were examined by reverse transcription-polymerase chain reaction amplification. The secreted uPA antigen was measured by ELISA. To evaluate the involvement of COX-2 and PGE2 pathway in H. pylori-induced uPA and uPAR expressions, we examined the effects of COX-2 inhibitor and PGE2 receptor antagonist on H. pylori-induced uPA and uPAR expression in the gastric cancer cells.


RESULTS
The expressions of both uPA and uPAR mRNAs in the gastric cancer cells increased obviously (12-fold and 3-fold, respectively) with H. pylori stimulation. The amount of uPA antigen into the culture medium increased dramatically with H. pylori stimulation. The COX-2 expression level in the gastric cancer cells increased remarkably with H. pylori stimulation. H. pylori-induced uPA and uPAR expression levels were suppressed with COX2 inhibitor treatment. The amount of PGE2 antigen into the culture medium increased dramatically 24 hours after H. pylori stimulation. The gastric cancer cells expressed EP2 and EP4 subtypes. EP2 receptor antagonist suppressed the H. pylori-induced uPA and uPAR expressions in the gastric cancer cells.


CONCLUSIONS
Our results indicated that COX2-PGE2 pathway may be involved in H. pylori-associated uPA and uPAR induction, and that COX-2 inhibitor or EP2 receptor antagonist may inhibit angiogenesis and tumor invasion via suppression of the uPA system.
Iwamoto
Junichi
J
Department of Gastroenterology, Kasumigaura Hospital, Tokyo Medical University, Tokyo, Japan. junnki@dg.mbn.or.jp
Mizokami
Yuji
Y
Takahashi
Kimiko
K
Matsuoka
Takeshi
T
Matsuzaki
Yasushi
Y
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors; D058307:Receptors, Prostaglandin E, EP2 Subtype; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000382:microbiology* / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D044004:Xanthones / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; C524898:PLAUR protein, human; C545644:PTGER2 protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D055293:Receptors, Urokinase Plasminogen Activator; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D051546:Cyclooxygenase 2; D014568:Urokinase-Type Plasminogen Activator; D015232:Dinoprostone