title: Apurinic/apyrimidinic endonuclease-1 is associated with angiogenesis and VEGF production via upregulation of COX-2 expression in esophageal cancer tissues.
abstract: Apurinic/apyrimidinic endonuclease-1 (APE-1) is a key enzyme responsible for DNA base excision repair and is also a multifunctional protein such as redox effector for several transcriptional factors. Our study was designed to investigate APE-1 expression and to study its interaction with cyclooxygenase (COX)-2 expression and VEGF production in the esophageal cancer. The expression of APE-1, COX-2, monocyte chemoattractant protein (MCP)-1, CC-chemokine receptor (CCR)2, and VEGF were evaluated by immunohistochemistry in 65 human esophageal squamous cell carcinoma (ESCC) tissues. Real-time PCR and Western blotting were performed to detect mRNA and protein expression of APE-1 and p-signal transducer and activator of transcription 3 (STAT3) expression in MCP-1-stimulated ESCC cell lines (KYSE 220 and EC-GI-10). siRNA for APE-1 was treated to determine the role of APE-1 in the regulation of COX-2 expression, VEGF production, and antiapoptotic effect against cisplatin. In human ESCC tissues, nuclear localization of APE-1 was observed in 92.3% (60/65) of all tissues. There was a significant relationship (P = 0.029, R = 0.49) between nuclear APE-1 and cytoplasmic COX-2 expression levels in the esophageal cancer tissues. In KYSE 220 and EC-GI-10 cells, MCP-1 stimulation significantly increased mRNA and protein expression of APE-1. Treatment with siRNA for APE-1 significantly inhibited p-STAT3 expression levels in MCP-1-stimulated cells. Furthermore, treatment of siRNA for APE-1 significantly reduced COX-2 expression and VEGF production in MCP-1-stimulated esophageal cancer cell lines. Treatment with APE-1 siRNA significantly increased apoptotic levels in cisplatin-incubated KYSE 220 and EC-GI-10 cells. We concluded that APE-1 is overexpressed and associated with COX-2 expression and VEGF production in esophageal cancer tissues.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagoya
authors.forename: Seiji
authors.initials: S
authors.lastname: Futagami
authors.forename: Mayumi
authors.initials: M
authors.lastname: Shimpuku
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tatsuguchi
authors.forename: Taiga
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamawaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodaka
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kawagoe
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Watarai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Makino
authors.forename: Masao
authors.initials: M
authors.lastname: Miyashita
authors.forename: Shinichi
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Crowe
authors.forename: Choitsu
authors.initials: C
authors.lastname: Sakamoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: apurinic/apyrimidinic endonuclease-1; cyclooxygenase-2; esophageal cancer; monocyte chemoattractant protein-1; vascular endothelial growth factor