title: Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion.
abstract: Changes in cellular oxygen tension play important roles in physiological processes including development and pathological processes such as tumor promotion. The cellular adaptations to sustained hypoxia are mediated by hypoxia-inducible factors (HIFs) to regulate downstream target gene expression. With hypoxia, the stabilized HIF-α and aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-β) heterodimer bind to hypoxia response elements (HREs) and regulate expression of target genes. Here, we report that WNT11 is induced by hypoxia in many cell types, and that transcription of WNT11 is regulated primarily by HIF-1α. We observed induced WNT11 expression in the hypoxic area of allograft tumors. In addition, in mice bearing orthotopic malignant gliomas, inhibition with bevacizumab of vascular endothelial growth factor, which is an important stimulus for angiogenesis, increased nuclear HIF-1α and HIF-2α, and expression of WNT11. Gain- and loss-of-function approaches revealed that WNT11 stimulates proliferation, migration and invasion of cancer-derived cells, and increases activity of matrix metalloproteinase (MMP)-2 and 9. Since tumor hypoxia has been proposed to increase tumor aggressiveness, these data suggest WNT11 as a possible target for cancer therapies, especially for tumors treated with antiangiogenic therapy.
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Hiroyuki
authors: H
authors: Mori
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Yao
authors: Y
authors: Yao
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Brian S
authors: BS
authors: Learman
authors: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors: Kazuhiko
authors: K
authors: Kurozumi
authors: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors: Joji
authors: J
authors: Ishida
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Sadeesh K
authors: SK
authors: Ramakrishnan
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Katherine A
authors: KA
authors: Overmyer
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Xiang
authors: X
authors: Xue
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.|BHF/University Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
authors: William P
authors: WP
authors: Cawthorn
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Michael A
authors: MA
authors: Reid
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Matthew
authors: M
authors: Taylor
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.|College of Animal Science and Technology, Northwest Agriculture and Forestry University, Yangling, Shaanxi, PRC.
authors: Xiaomin
authors: X
authors: Ning
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors: Yatrik M
authors: YM
authors: Shah
authors: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors: Ormond A
authors: OA
authors: MacDougald
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis; D000068258:Bevacizumab / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010100:Oxygen / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; C497397:Arnt protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse; C467480:vascular endothelial growth factor A, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000068258:Bevacizumab; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse; D010100:Oxygen