Research of promotion and Support Headquarters

SUGIHARA KAZUHIRO

  (杉原 一廣)

Profile Information

Affiliation
Fujita Health University
Degree
医学博士(慶應義塾大学)

Other name(s) (e.g. nickname)
https://bantane.fujita-hu.ac.jp/department/obstericians.html
J-GLOBAL ID
200901012107446377
researchmap Member ID
5000096026

External link

日本産科婦人科学会 産婦人科専門医
日本産科婦人科学会 産婦人科指導医
日本生殖医学会認定 生殖医療専門医
日本生殖医学会認定 生殖医療指導医
日本婦人科腫瘍学会 婦人科腫瘍専門医
日本婦人科腫瘍学会 婦人科腫瘍指導医
日本がん治療認定医機構 がん治療認定医
日本がん治療認定医機構 暫定教育医

 


Research History

 15

Major Papers

 60
  • K. Sugihara, Y. Kobayashi, A. Suzuki, N. Tamura, K. Motamedchaboki, C. T. Huang, T. O. Akama, J. Pecotte, P. Frost, C. Bauer, J. B. Jimenez, J. Nakayama, D. Aoki, M. N. Fukuda
    Nature Communications, 5(448) 1-9, Jul 22, 2014  Peer-reviewed
    © 2014 Macmillan Publishers Limited. All rights reserved. Endometriosis is a common gynaecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with nonsteroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide-gated channel β3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.
  • Shingo Hatakeyama, Kazuhiro Sugihara, Toshiaki K Shibata, Jun Nakayama, Tomoya O Akama, Naoaki Tamura, Shuk-Man Wong, Andrey A Bobkov, Yutaka Takano, Chikara Ohyama, Minoru Fukuda, Michiko N Fukuda
    Proc. Natl. Acad. Sci. USA (PNAS), 108(49) 19587-92, Dec 6, 2011  Peer-reviewed
    Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs.
  • Shingo Hatakeyama, Kazuhiro Sugihara, Jun Nakayama, Tomoya O Akama, Shuk-Man Annie Wong, Hiroto Kawashima, Jianing Zhang, David F Smith, Chikara Ohyama, Minoru Fukuda, Michiko N Fukuda
    Proc. Natl. Acad. Sci. USA (PNAS), 106(9) 3095-100, Mar 3, 2009  Peer-reviewed
    Cell surfaces of epithelial cancer are covered by complex carbohydrates, whose structures function in malignancy and metastasis. However, the mechanism underlying carbohydrate-dependent cancer metastasis has not been defined. Previously, we identified a carbohydrate-mimicry peptide designated I-peptide, which inhibits carbohydrate-dependent lung colonization of sialyl Lewis X-expressing B16-FTIII-M cells in E/P-selectin doubly-deficient mice. We hypothesized that lung endothelial cells express an unknown carbohydrate receptor, designated as I-peptide receptor (IPR), responsible for lung colonization of B16-FTIII-M cells. Here, we visualized IPR by in vivo biotinylation, which revealed that the major IPR is a group of 35-kDa proteins. IPR proteins isolated by I-peptide affinity chromatography were identified by proteomics as Ser/Arg-rich alternative pre-mRNA splicing factors or Sfrs1, Sfrs2, Sfrs5, and Sfrs7 gene products. Bacterially expressed Sfrs1 protein bound to B16-FTIII-M cells but not to parental B16 cells. Recombinant Sfrs1 protein bound to a series of fucosylated oligosaccharides in glycan array and plate-binding assays. When anti-Sfrs antibodies were injected intravenously into mice, antibodies labeled a subset of lung capillaries. Anti-Sfrs antibodies inhibited homing of I-peptide-displaying phage to the lung colonization of B16-FTIII-M cells in vivo in the mouse. These results strongly suggest that Sfrs proteins are responsible for fucosylated carbohydrate-dependent lung metastasis of epithelial cancers.
  • Kazuhiro Sugihara, Daijiro Sugiyama, James Byrne, Don P Wolf, Kevin P Lowitz, Yoichi Kobayashi, Maryam Kabir-Salmani, Daita Nadano, Daisuke Aoki, Shiro Nozawa, Jun Nakayama, Tomas Mustelin, Erkki Ruoslahti, Naoto Yamaguchi, Michiko N Fukuda
    Proc. Natl. Acad. Sci. USA (PNAS), 104(10) 3799-804, Mar 6, 2007  Peer-reviewed
    During human embryo implantation, trophectoderm mediates adhesion of the blastocyst to the uterine epithelium. The rapid growth of the embryo and invasion of the maternal tissue suggest adhesion-induced activation of the embryonal cells. We show here that ligation of trophinin, a homophilic cell adhesion molecule expressed on trophoblastic cells, induces tyrosine phosphorylation in trophinin-expressing trophoblastic HT-H cells. The phosphorylation could be induced in HT-H cells with the binding of trophinin-expressing cells or anti trophinin antibodies. Trophinin-dependent tyrosine phosphorylation was associated with actin reorganization. We also isolated trophinin-binding peptides from phage libraries. These peptides exhibited the consensus sequence GWRQ and seemed to reproduce the effects of trophinin-mediated cell adhesion. Upon binding of a GWRQ peptide, HT-H cells became highly proliferative and motile. HT-H cells expressed ErbB family receptors and bound EGF and heparin-binding EGF-like growth factor (HB-EGF), but ErbB family receptor phosphorylation in these cells required GWRQ. In the absence of GWRQ, trophinin interacted with the cytoplasmic protein bystin, which binds to ErbB4 and blocks its autophosphorylation. In HT-H cells, GWRQ peptide dissociated trophinin from bystin, and ErbB4 was activated. Culturing monkey blastocysts in the presence of the peptide increased total number and motility of the trophectoderm cells. These results suggest that trophinin-mediated cell adhesion functions as a molecular switch for trophectoderm activation in human embryo implantation.
  • Tomoya O Akama, Hiroaki Nakagawa, Kazuhiro Sugihara, Sonoko Narisawa, Chikara Ohyama, Shin-Ichiro Nishimura, Deborah A O'Brien, Kelley W Moremen, Jose Luis Millan, Michiko N Fukuda
    Science, 295(5552) 124-7, Jan 4, 2002  Peer-reviewed
    Spermatogenesis is a precisely regulated process in which the germ cells closely interact with Sertoli cells. The molecular basis of this cell-cell adhesion is unknown. Here, we demonstrate that targeted disruption of Man2a2, a gene encoding alpha-mannosidase IIx (MX), an enzyme that forms intermediate asparagine-linked carbohydrates (N-glycans), results in Man2a2 null males that are largely infertile. The Man2a2 null spermatogenic cells fail to adhere to Sertoli cells and are prematurely released from the testis to epididymis. We identified an N-glycan structure that plays a key role in germ cell-Sertoli cell adhesion and showed that a specific carbohydrate was required for spermatogenesis.
  • Kazuhiro Sugihara, Shiro Asano, Kenichi Tanaka, Akihiro Iwamatsu, Katsuya Okawa, Yasutaka Ohta
    Nature cell biology, 4(1) 73-8, Jan, 2002  Peer-reviewed
    The Ras-related small GTPase RalA is involved in controlling actin cytoskeletal remodelling and vesicle transport in mammalian cells. We identified the mammalian homologue of Sec5, a subunit of the exocyst complex determining yeast cell polarity, as a specific binding partner for GTP-ligated RalA. Inhibition of RalA binding to Sec5 prevents filopod production by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and by activated forms of RalA and Cdc42, signalling intermediates downstream of these inflammatory cytokines. We propose that the RalA-exocyst complex interaction integrates the secretory and cytoskeletal pathways.

Misc.

 40

Presentations

 6

Works

 4
  • 中日新聞
    2015 Others
    「子宮内膜症治療薬」が我が国主導の創薬支援(AMED)に採択
  • 腹膜子宮内膜症の治療法となる可能性のあるアポトーシス誘導性ペプチドの開発
    2014 Others
    http://www.natureasia.com/ja-jp/ncomms/abstracts/55462
  • 日経バイオテク, 読売新聞, 中日新聞, 静岡新聞, 共同通信
    Nov, 2011 Others
    「がんで増生する新生血管を標的とするペプチド配列を見出しました」
  • 中日新聞
    2009 Others
    「癌転移の分子機構」 中日新聞1面トップ記事

Major Research Projects

 22