Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy

// Jianying Guo 1,4 , Satoru Shinriki 1 , Yu Su 4 , Takuya Nakamura 5 , Mitsuhiro Hayashi 6 , Yukimoto Tsuda 7 , Yoshitaka Murakami 7 , Masayoshi Tasaki 1,4 , Takuichiro Hide 8 , Tatsuya Takezaki 8 , Jun-ichi Kuratsu 8 , Satoshi Yamashita 4 , Mitsuharu Ueda 4 , Jian-Dong Li 9 , Yukio Ando 4 and Hirofumi Jono 2,3 1 Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 2 Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan 3 Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan 4 Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 5 Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 6 Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 7 School of Medicine, Kumamoto University, Kumamoto, Japan 8 Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 9 Center for Inflammation, Immunity and Infection and Department of Biology, Georgia State University, Atlanta, Georgia Correspondence: Hirofumi Jono, email: // Yukio Ando, email: // Keywords : bevacizumab, CYLD, glioblastoma, hypoxia, inflammation Received : May 11, 2014 Accepted : July 13, 2014 Published : July 14, 2014 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.