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Carcinogenesis Advance Access published online on October 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn236
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells

Jung-Min Oh1, Su-Hyeong Kim1, Yun-Il Lee2, Miran Seo1, So-Young Kim1, Yong-Sang Song1,3, Woo-Ho Kim4 and Yong-Sung Juhnn1,2

1 Interdisciplinary Graduate Program in Tumor Biology, Cancer Research Institute
2 Department of Biochemistry and Molecular Biology
3 Department of Obstetrics and Gynecology
4 Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea

To whom correspondence should be addressed: Yong-Sung Juhnn, Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-799, Republic of Korea. Tel. 82-2-740-8247; FAX. 82-2-744-4534; E-mail. juhnn{at}snu.ac.kr

Human papillomavirus (HPV) is the major cause of uterine cervical cancer, but the role of the HPV E5 in carcinogenesis is not clearly understood. Prostaglandins are known to contribute to carcinogenesis of cervical cancer, and we therefore investigated the effect of HPV16 E5 on the expression of prostaglandin E2 (PGE2) receptors and underlying mechanisms. Stable expression of the E5 induced expression of the EP4 subtype of PGE2 receptors in C33A cervical cancer cells, and transfection of E5 siRNA decreased it. EP4 protein expression was increased in human cervical cancer tissues, and EP4 mediated E5-induced increase in anchorage-independent colony formation and VEGF expression. E5 induced COX-2 expression, and COX-2 increased PGE2 secretion and EP4 expression. The induction of EP4 by PGE2 and E5 was inhibited by an EP4 antagonist, inhibitors of cAMP dependent protein kinase or phosphatidylinositol 3-kinase, and a cAMP response element (CRE) decoy. E5 increased the luciferase expression controlled by a variant CRE of the EP4 promoter, and it also increased the binding of CREB to oligonucleotides containing this CRE. We conclude that the HPV16 E5 protein induces EP4 receptor protein in cervical cancer cells, and that this induction involves EGFR, COX-2, PGE2, EP2 and EP4, PKA, CREB, and CRE.

Key Words: human papillomavirus • E5 • EP4 • cyclic AMP response element • uterine cervical cancer

Received July 23, 2008; revised September 27, 2008; accepted September 28, 2008.


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