Apurinic/apyrimidinic endonuclease-1 is associated with angiogenesis and VEGF production via upregulation of COX-2 expression in esophageal cancer tissues

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 306; no. 3; pp. G183 - G190
• Main Authors: Nagoya, Hiroyuki, Futagami, Seiji, Shimpuku, Mayumi, Tatsuguchi, Atsushi, Wakabayashi, Taiga, Yamawaki, Hiroshi, Kodaka, Yasuhiro, Kawagoe, Tetsuro, Watarai, Yasuhiko, Makino, Hiroshi, Miyashita, Masao, Tsuchiya, Shinichi, Crowe, Sheila E, Sakamoto, Choitsu
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2014
• Series: Physiology and GI Cancer
• Subjects: Aged; Aged, 80 and over; Angiogenesis; Call for Papers; Carcinoma, Squamous Cell - blood supply; Carcinoma, Squamous Cell - diagnosis; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Cyclooxygenase 2 - metabolism; DNA repair; DNA Repair - physiology; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Enzymes; Esophageal cancer; Esophageal Neoplasms - blood supply; Esophageal Neoplasms - diagnosis; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neovascularization, Pathologic; Protein expression; Up-Regulation - physiology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; monocyte chemoattractant protein-1; apurinic/apyrimidinic endonuclease-1; esophageal cancer; vascular endothelial growth factor; cyclooxygenase-2
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00057.2013

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.