title: Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy.
abstract: Cylindromatosis (CYLD) is a tumor suppressor that regulates signaling pathways by acting as a deubiquitinating enzyme. CYLDdown-regulation occurred in several malignancies, with tumor-promoting effects. Although we found loss of CYLD expression in hypoxic regions of human glioblastoma multiforme (GBM), the most aggressive brain tumor, biological roles of CYLD in GBM remain unknown. This study aimed to determine the biological significance of CYLD down-regulation to GBM progression and therapy. CYLD mRNA transcription was dramatically down-regulated in hypoxic GBM cells, consistent with our clinical observations of human GBM tissues. Hypoxia enhanced both basal and tumor necrosis factor-α-induced expression of various proinflammatory cytokines, whereas CYLD overexpression strongly counteracted these responses. In addition, chronic anti-angiogenic therapy with bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, with enhanced hypoxia produced responses similar to these CYLD-regulated proinflammatory responses in a xenograft mouse model. Histologically, CYLD clearly prevented massive immune cell infiltration surrounding necrotic regions, and pseudopalisades appeared in bevacizumab-treated control tumors. Furthermore, CYLD overexpression, which had no impact on survival by itself, significantly improved the prosurvival effect of bevacizumab. These data suggest that CYLD down-regulation is crucial for hypoxia-mediated inflammation in GBM, which may affect the long-term efficacy of anti-VEGF therapy.
authors: Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Jianying
authors: J
authors: Guo
authors: Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Satoru
authors: S
authors: Shinriki
authors: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Yu
authors: Y
authors: Su
authors: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Takuya
authors: T
authors: Nakamura
authors: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Mitsuhiro
authors: M
authors: Hayashi
authors: School of Medicine, Kumamoto University, Kumamoto, Japan.
authors: Yukimoto
authors: Y
authors: Tsuda
authors: School of Medicine, Kumamoto University, Kumamoto, Japan.
authors: Yoshitaka
authors: Y
authors: Murakami
authors: Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Masayoshi
authors: M
authors: Tasaki
authors: Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Takuichiro
authors: T
authors: Hide
authors: Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Tatsuya
authors: T
authors: Takezaki
authors: Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Jun-Ichi
authors: J
authors: Kuratsu
authors: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Satoshi
authors: S
authors: Yamashita
authors: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Mitsuharu
authors: M
authors: Ueda
authors: Center for Inflammation, Immunity and Infection and Department of Biology, Georgia State University, Atlanta, Georgia.
authors: Jian-Dong
authors: JD
authors: Li
authors: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Yukio
authors: Y
authors: Ando
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan.
authors: Hirofumi
authors: H
authors: Jono
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D000074749:Deubiquitinating Enzyme CYLD; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD