Prostaglandin E2 upregulates survivin expression via the EP1 receptor in hepatocellular carcinoma cells.
OBJECTIVE
Cyclooxygenase-2 (COX-2)-controlled production of prostaglandin E(2) (PGE(2)) has been implicated in cell growth and metastasis in many cancers. Recent studies have found that COX-2 is co-expressed with survivin in many cancers. Survivin is a member of the inhibitor-of-apoptosis protein family. Some COX-2 inhibitors (e.g., celecoxib) can reduce the expression of survivin. However, little is known about the mechanism of PGE(2)-mediated expression of survivin. This study was designed to uncover the effect of PGE(2) on survivin expression in hepatocellular carcinoma cells.


METHODS
The effects of PGE(2) and EP1 agonist on survivin expression were examined in HUH-7 and HepG2 cells. Plasmid transfection and EP1 siRNA were used to regulate the expression of COX-2 and the EP1 receptor protein.


RESULTS
PGE(2) treatment increased survivin expression 2.3-fold. COX-2 overexpression resulted in a similar level of survivin upregulation. However, this effect was suppressed by treatment with celecoxib. EP1 receptor transfection or treatment with a selective EP1 agonist mimicked the effect of PGE(2) treatment. Conversely, the PGE(2)-induced upregulation of survivin was blocked by treatment with a selective EP1 antagonist or siRNA against the EP1 receptor. The phosphorylation of EGFR and Akt were elevated in EP1 agonist-treated cells, and both EGFR and PI3K inhibitors suppressed the upregulation of survivin induced by PGE(2) or EP1 agonist.


CONCLUSIONS
PGE(2) regulates survivin expression in hepatocellular carcinoma cells through the EP1 receptor by activating the EGFR/PI3K pathway. Targeting the PGE(2)/EP1/survivin signaling pathway may aid the development of new therapeutic strategies for both the prevention and treatment of this cancer.
Bai
Xiao-Ming
XM
Cancer Center, Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing 210029, China. Baixiaoming@njmu.edu.cn
Jiang
Hui
H
Ding
Jing-Xian
JX
Peng
Tao
T
Ma
Juan
J
Wang
Yao-Hui
YH
Zhang
Li
L
Zhang
Hai
H
Leng
Jing
J
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D010957:Plasmids; D034622:RNA Interference; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin; D014162:Transfection; D015854:Up-Regulation
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D000077022:Survivin; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D015232:Dinoprostone