Curriculum Vitaes

Saya Hideyuki

  (佐谷 秀行)

Profile Information

Affiliation
Professor (Director), Oncology Innovation Center, Fujita Health University
Professor, Keio University

Researcher number
80264282
J-GLOBAL ID
200901021585172745
researchmap Member ID
1000222498

Hideyuki Saya MD, PhD graduated from Kobe University School of Medicine in 1981 and was Resident in the Neurosurgery until 1983. After which he joined the Graduate School of Medical Sciences granting his PhD in 1987. He studied as a Postdoctoral Fellow in UCSF until 1988 then was appointed Assistant Professor at the Neuro-Oncology, M.D. Anderson Cancer Center. Houston, TX. From 1994 to 2006 he was Professor, Kumamoto University School of Medicine before taking his current position in Keio University School of Medicine in 2007. He is currently a vice president of Keio University Hospital and Director of Clinical and Translational Research Center.

Papers

 447
  • Takatsune Shimizu, Kiyomi Kimura, Eiji Sugihara, Sayaka Yamaguchi‐Iwai, Hiroyuki Nobusue, Oltea Sampetrean, Yuji Otsuki, Yumi Fukuchi, Kaori Saitoh, Keiko Kato, Tomoyoshi Soga, Akihiro Muto, Hideyuki Saya
    Journal of Orthopaedic Research, Mar 26, 2021  
  • Ikue Tai-Nagara, Yukiko Hasumi, Dai Kusumoto, Hisashi Hasumi, Keisuke Okabe, Tomofumi Ando, Fumio Matsuzaki, Fumiko Itoh, Hideyuki Saya, Chang Liu, Wenling Li, Yoh-suke Mukouyama, W. Marston Linehan, Xinyi Liu, Masanori Hirashima, Yutaka Suzuki, Shintaro Funasaki, Yorifumi Satou, Mitsuko Furuya, Masaya Baba, Yoshiaki Kubota
    Nature Communications, 11(1), Dec, 2020  
    <title>Abstract</title>Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.
  • Tanno N, Kuninaka S, Fujimura S, Takemoto K, Okamura K, Takeda N, Araki K, Araki M, Saya H, Ishiguro K.i
    Scientific Reports, 10(1) 10094-10094, Dec 1, 2020  
    © 2020, The Author(s). FZR1/CDH1 is an activator of Anaphase promoting complex/Cyclosome (APC/C), best known for its role as E3 ubiquitin ligase that drives the cell cycle. APC/C activity is regulated by CDK-mediated phosphorylation of FZR1 during mitotic cell cycle. Although the critical role of FZR1 phosphorylation has been shown mainly in yeast and in vitro cell culture studies, its biological significance in mammalian tissues in vivo remained elusive. Here, we examined the in vivo role of FZR1 phosphorylation using a mouse model, in which non-phosphorylatable substitutions were introduced in the putative CDK-phosphorylation sites of FZR1. Although ablation of FZR1 phosphorylation did not show substantial consequences in mouse somatic tissues, it led to severe testicular defects resulting in male infertility. In the absence of FZR1 phosphorylation, male juvenile germ cells entered meiosis normally but failed to enter meiosis II or form differentiated spermatids. In aged testis, male mutant germ cells were overall abolished, showing Sertoli cell-only phenotype. In contrast, female mutants showed apparently normal progression of meiosis. The present study demonstrated that phosphorylation of FZR1 is required for temporal regulation of APC/C activity at meiosis II entry, and for maintenance of spermatogonia, which raised an insight into the sexual dimorphism of FZR1-regulation in germ cells.
  • Shono K, Yamaguchi I, Mizobuchi Y, Kagusa H, Sumi A, Fujihara T, Nakajima K, Kitazato K.T, Matsuzaki K, Saya H, Takagi Y
    Scientific Reports, 10(1), Dec 1, 2020  
    © 2020, The Author(s). Glioblastoma multiforme involves glioma stem cells (GSCs) that are resistant to various therapeutic approaches. Here, we studied the importance of paracrine signaling in the glioma microenvironment by focusing on the celecoxib-mediated role of chemokines C–C motif ligand 2 (CCL2), C-X-C ligand 10 (CXCL10), and their receptors, CCR2 and CXCR3, in GSCs and a GSC-bearing malignant glioma model. C57BL/6 mice were injected with orthotopic GSCs intracranially and divided into groups administered either 10 or 30 mg/kg celecoxib, or saline to examine the antitumor effects associated with chemokine expression. In GSCs, we analyzed cell viability and expression of chemokines and their receptors in the presence/absence of celecoxib. In the malignant glioma model, celecoxib exhibited antitumor effects in a dose dependent manner and decreased protein and mRNA levels of Ccl2 and CxcL10 and Cxcr3 but not of Ccr2. CCL2 and CXCL10 co-localized with Nestin+ stem cells, CD16+ or CD163+ macrophages and Iba-1+ microglia. In GSCs, celecoxib inhibited Ccl2 and Cxcr3 expression in a nuclear factor-kappa B-dependent manner but not Ccr2 and CxcL10. Moreover, Ccl2 silencing resulted in decreased GSC viability. These results suggest that celecoxib-mediated regulation of the CCL2/CCR2 and CXCL10/ CXCR3 axes may partially contribute to glioma-specific antitumor effects.
  • Koike N, Kota R, Naito Y, Hayakawa N, Matsuura T, Hishiki T, Onishi N, Fukada J, Suematsu M, Shigematsu N, Saya H, Sampetrean O
    Communications Biology, 3(1), Dec 1, 2020  
    © 2020, The Author(s). Under hypoxic conditions, nitroimidazoles can replace oxygen as electron acceptors, thereby enhancing the effects of radiation on malignant cells. These compounds also accumulate in hypoxic cells, where they can act as cytotoxins or imaging agents. However, whether these effects apply to cancer stem cells has not been sufficiently explored. Here we show that the 2-nitroimidazole doranidazole potentiates radiation-induced DNA damage in hypoxic glioma stem cells (GSCs) and confers a significant survival benefit in mice harboring GSC-derived tumors in radiotherapy settings. Furthermore, doranidazole and misonidazole, but not metronidazole, manifested radiation-independent cytotoxicity for hypoxic GSCs that was mediated by ferroptosis induced partially through blockade of mitochondrial complexes I and II and resultant metabolic alterations in oxidative stress responses. Doranidazole also limited the growth of GSC-derived subcutaneous tumors and that of tumors in orthotopic brain slices. Our results thus reveal the theranostic potential of 2-nitroimidazoles as ferroptosis inducers that enable targeting GSCs in their hypoxic niche.

Misc.

 80

Teaching Experience

 33

Research Projects

 4