Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy.
作者： Jianying Guo , Satoru Shinriki , Yu Su , Takuya Nakamura , Mitsuhiro Hayashi
关键词: Vascular endothelial growth factor A 、 Oncology 、 Hypoxia (medical) 、 Brain tumor 、 Pathology 、 Biology 、 Tumor necrosis factor alpha 、 Bevacizumab 、 Internal medicine 、 Inflammation 、 Proinflammatory cytokine 、 Deubiquitinating Enzyme CYLD
摘要: // Jianying Guo 1,4 , Satoru Shinriki 1 Yu Su 4 Takuya Nakamura 5 Mitsuhiro Hayashi 6 Yukimoto Tsuda 7 Yoshitaka Murakami Masayoshi Tasaki Takuichiro Hide 8 Tatsuya Takezaki Jun-ichi Kuratsu Satoshi Yamashita Mitsuharu Ueda Jian-Dong Li 9 Yukio Ando and Hirofumi Jono 2,3 Department of Diagnostic Medicine, Graduate School Medical Sciences, Kumamoto University, Kumamoto, Japan 2 Clinical Pharmaceutical 3 Pharmacy, University Hospital, Neurology, Oral Maxillofacial Surgery, Breast Endocrine Neurosurgery, Center for Inflammation, Immunity Infection Biology, Georgia State Atlanta, Correspondence: Jono, email: Ando, Keywords : bevacizumab, CYLD, glioblastoma, hypoxia, inflammation Received May 11, 2014 Accepted July 13, Published 14, Abstract Cylindromatosis (CYLD) is a tumor suppressor that regulates signaling pathways by acting as deubiquitinating enzyme. CYLDdown-regulation occurred in several malignancies, with tumor-promoting effects. Although we found loss CYLD expression hypoxic regions human glioblastoma multiforme (GBM), the most aggressive brain tumor, biological roles GBM remain unknown. This study aimed to determine significance down-regulation progression therapy. mRNA transcription was dramatically down-regulated cells, consistent our clinical observations tissues. Hypoxia enhanced both basal necrosis factor-α-induced various proinflammatory cytokines, whereas overexpression strongly counteracted these responses. In addition, chronic anti-angiogenic therapy an anti-vascular endothelial growth factor (VEGF) antibody, hypoxia produced responses similar CYLD-regulated xenograft mouse model. Histologically, clearly prevented massive immune cell infiltration surrounding necrotic regions, pseudopalisades appeared bevacizumab-treated control tumors. Furthermore, overexpression, which had no impact on survival itself, significantly improved prosurvival effect bevacizumab. These data suggest crucial hypoxia-mediated GBM, may affect long-term efficacy anti-VEGF
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