VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts

Wang,Jia; Ikeda,Ryuji; Che,Xiao-Fang; Ooyama,Akio; Yamamoto,Masatatsu; Furukawa,Tatsuhiko; Hasui,Kazuhisa; Zheng,Chun-Lei; Tajitsu,Yusuke; Oka,Toshinori; Tabata,Sho; Nishizawa,Yukihiko; Eizuru,Yoshito; Akiyama,Shin-Ichi

doi:10.3892/ijo.2013.1994

VEGF expression is augmented by hypoxia‑induced PGIS in human fibroblasts

Authors:
- Jia Wang
- Ryuji Ikeda
- Xiao-Fang Che
- Akio Ooyama
- Masatatsu Yamamoto
- Tatsuhiko Furukawa
- Kazuhisa Hasui
- Chun-Lei Zheng
- Yusuke Tajitsu
- Toshinori Oka
- Sho Tabata
- Yukihiko Nishizawa
- Yoshito Eizuru
- Shin-Ichi Akiyama
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Affiliations: Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan, Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima 890-8520, Japan, Department of Molecular Oncology, Division of Cancer Genetics, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima 890-8520, Japan, Taiho Pharmaceutical. Co. Ltd, Personalized Medicine Research Laboratory, Shanghai 200032, P.R. China, Department of Immunology, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima 890-8520, Japan, Department of Medical Oncology, Cancer Hospital, Fudan University, Shanghai 200032, P.R. China, Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima 890-8520, Japan, Department of Respiratory Medicine and Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
Published online on: June 27, 2013 https://doi.org/10.3892/ijo.2013.1994
Pages: 746-754

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Abstract

Prostacyclin synthase (PGIS or PTGIS) is an enzyme that catalyses the conversion of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2). PGI2 promotes cancer growth by activating peroxisome proliferator-activated receptor δ (PPARδ), and increases the expression levels of the pro-angiogenic factor vascular endothelial growth factor (VEGF). We found that the expression of the PGIS gene was enhanced in WI-38, TIG-3-20 and HEL human lung fibroblast cells and two cancer cell lines (NB-1 and G361) under hypoxic conditions. The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI-38 cells. The induced PGIS had an enzymatic activity since the intracellular level of 6-keto-prostaglandin, a useful marker of PGI2 biosynthesis in vivo, was increased with the increasing levels of PGIS. Expression of VEGF was increased in parallel with PGIS induction under hypoxic conditions. PGIS knockdown resulted in the decreased expression of VEGF mRNA. Since VEGF is a known PPARδ target gene, we examined the effects of siRNAs targeting PPARδ on the expression of VEGF under hypoxic conditions. Knockdown of PPARδ suppressed the expression of VEGF under hypoxic conditions in WI-38 cells. These findings suggest that PGIS is induced by hypoxia and regulates the expression of VEGF in fibroblasts. Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis.

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