title: VEGF expression is regulated by HIF-1α and ARNT in 3D KYSE-70, esophageal cancer cell spheroids.
abstract: In 3D cultured cell systems, the cells form 3D spheroids that mimic cancer cell spheroids in vivo. Cancer cells form cell spheroids as they grow. The in vivo spheroids do not contain a vascular network; therefore, oxygen and nutrition supplies are insufficient. Specifically, the cells in the core region of the cluster are exposed to higher stress levels than the cells in the outer spheroid layer. As a result, the cells in the spheroid are exposed to low nutrition and hypoxia conditions. To overcome these shortages, angiogenesis is induced in cancer spheroids in vivo. Vascular endothelial growth factor (VEGF) is an important molecule involved in angiogenesis. VEGF is secreted by cancer cells in vivo in response to stress conditions such as hypoxia. VEGF expression in cancer cells is mediated by hypoxia-inducible factor 1α (HIF1α), which accumulates in cancer cells during hypoxia. In this report, we show that VEGF expression is regulated by HIF1α and that VEGF is secreted to the outside of the spheroid in vitro. Several investigators have reported that HIF1α forms a protein-protein complex with aryl hydrocarbon receptor translocator (ARNT). We report here that not only HIF1α but also ARNT regulates VEGF expression in 3D cancer spheroids. Our results suggest the utility of the in vitro 3D cancer spheroid model for investigating angiogenesis in cancerous tissues.
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan. jterashi@iwate-med.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Terashima
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Sampei
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan.
authors.forename: Mei
authors.initials: M
authors.lastname: Iidzuka
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ohsakama
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan.|Department of Pharmacy, Iwate Medical University Hospital, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Tachikawa
authors.affiliation: Department of Pharmacy, Iwate Medical University Hospital, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Satoh
authors.affiliation: Department of Pharmacy, Iwate Medical University Hospital, 19-1 Uchimaru, Morioka, Iwate, 020-8505, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Kudo
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Habano
authors.affiliation: Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuda, Yahaba-CHO, Siwa-Gun, Iwate, 028-3694, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018874:Spheroids, Cellular; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497396:ARNT protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator
keywords: 3D culture; 3D spheroid; hypoxia-inducible factor 1α; vascular epithelial growth factor