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.
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 small interfering RNA (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 vascular endothelial growth factor expression. E5 induced cyclooxygenase-2 (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 cyclic adenosine monophosphate-dependent protein kinase or phosphatidylinositol 3-kinase, and a cyclic adenosine monophosphate 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 cyclic adenosine monophosphate response element binding protein (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 epidermal growth factor receptor, COX-2, PGE2, EP2 and EP4, protein kinase A, CREB and CRE.
Interdisciplinary Graduate Program in Tumor Biology, Cancer Research Institute, Seoul National University College of Medicine, Jongno-Gu, Seoul, Republic of Korea.
Jung-Min
JM
Oh
Su-Hyeong
SH
Kim
Yun-Il
YI
Lee
Miran
M
Seo
So-Young
SY
Kim
Yong-Sang
YS
Song
Woo-Ho
WH
Kim
Yong-Sung
YS
Juhnn
D001483:Base Sequence; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017931:DNA Primers; D015232:Dinoprostone / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D049449:Luminescence; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018078:Receptors, Prostaglandin E / Q000235:genetics*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology; D000086082:Viroporin Proteins
D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D051546:Cyclooxygenase 2; D017931:DNA Primers; D015232:Dinoprostone; D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C545650:PTGER4 protein, human; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins