Intracellular function of Sema4A in dendritic cells.

• Project/Area Number: 15K08423
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Osaka University
• Principal Investigator: Nojima Satoshi 大阪大学, 医学系研究科, 助教 (40528791)
• Co-Investigator(Renkei-kenkyūsha): KUMANOGOH Atsushi 大阪大学, 大学院医学系研究科, 教授 (10294125)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 自己免疫性疾患 / ANCA関連血管炎 / 免疫セマフォリン / 免疫学 / 好中球 / 血管炎 / 樹状細胞 / エクソソーム

Outline of Final Research Achievements

Since an interesting association between SEMA4D and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) was found, we studied the significance of SEMA4D in the pathogenesis of AAV. Serum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 successfully inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation.
Thus, neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.

Research Products

• [Journal Article] Anti-glypican-1 antibody-drug conjugate exhibits potent preclinical antitumor activity against glypican-1 positive uterine cervical cancer (2018)
  • Author(s): Matsuzaki S, Serada S, Hiramatsu K, Nojima S, Matsuzaki S, Ueda Y, Ohkawara T, Mabuchi S, Fujimoto M, Morii E, Yoshino K, Kimura T, Naka T.
  • Journal Title: Int J Cancer Volume: 142 Pages: 1056-1066
  • DOI: 10.1002/ijc.31124
  • Peer Reviewed
• [Journal Article] LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake (2018)
  • Author(s): Hiramatsu K, Serada S, Enomoto T, Takahashi Y, Nakagawa S, Nojima S, Morimoto A, Matsuzaki S, Yokoyama T, Takahashi T, Fujimoto M, Takemori H, Ueda Y, Yoshino K, Morii E, Kimura T, Naka T
  • Journal Title: Cancer Res. Volume: 78 Pages: 516-27
  • DOI: 10.1158/0008-5472.can-17-0910
  • Peer Reviewed / Open Access
• [Journal Article] Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate (2018)
  • Author(s): Park Haengki、Ohshima Kenji、Nojima Satoshi、Tahara Shinichiro、Kurashige Masako、Hori Yumiko、Okuzaki Daisuke、Wada Naoki、Ikeda Jun-ichiro、Morii Eiichi
  • Journal Title: Lab Invest. Volume: in press Pages: 449-461
  • DOI: 10.1038/s41374-017-0017-0
  • Peer Reviewed / Open Access
• [Journal Article] Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis (2017)
  • Author(s): Nishide M, Nojima S, Ito D, Takamatsu H, Koyama S, Kang S, Kimura T, Morimoto K, Hosokawa T, Hayama Y, Kinehara Y, Kato Y, Nakatani T, Nakanishi Y, Tsuda T, Park JH, Hirano T, Shima Y, Narazaki M, Morii E, Kumanogoh A.
  • Journal Title: Ann Rheum Dis. Volume: 76 Pages: 1440-1448
  • DOI: 10.1136/annrheumdis-2016-210706
  • Peer Reviewed
• [Journal Article] Glypican-1 targeted antibody-based therapy induces preclinical antitumor activity against esophageal squamous cell carcinoma (2017)
  • Author(s): Harada E, Serada S, Fujimoto M, Takahashi Y, Takahashi T, Hara H, Nakatsuka R, Sugase T, Nishigaki T, Saito Y, Hiramatsu K, Nojima S, Mitsuo R, Ohkawara T, Morii E, Mori M, Doki Y, Kaneda Y, Naka T.
  • Journal Title: Oncotarget Volume: 8 Pages: 24741-24752
  • DOI: 10.18632/oncotarget.15799
  • Peer Reviewed / Open Access
• [Journal Article] Lamtor1 Is Critically Required for CD4+ T Cell Proliferation and Regulatory T Cell Suppressive Function. (2017)
  • Author(s): Hosokawa T, Kimura T, Nada S, Okuno T, Ito D, Kang S, Nojima S, Yamashita K, Nakatani T, Hayama Y, Kato Y, Kinehara Y, Nishide M, Mikami N, Koyama S, Takamatsu H, Okuzaki D, Ohkura N, Sakaguchi S, Okada M, Kumanogoh A.
  • Journal Title: J Immunol Volume: 199 Pages: 2008-2019
  • DOI: 10.4049/jimmunol.1700157
  • Peer Reviewed / Open Access
• [Journal Article] CUBIC pathology: three-dimensional imaging for pathological diagnosis (2017)
  • Author(s): Nojima Satoshi、Susaki Etsuo A.、Yoshida Kyotaro、Takemoto Hiroyoshi、Tsujimura Naoto、Iijima Shohei、Takachi Ko、Nakahara Yujiro、Tahara Shinichiro、Ohshima Kenji、Kurashige Masako、Hori Yumiko、Wada Naoki、Ikeda Jun-ichiro、Kumanogoh Atsushi、Morii Eiichi、Ueda Hiroki R.
  • Journal Title: Sci Rep. Volume: 7 Pages: 9269-9269
  • DOI: 10.1038/s41598-017-09117-0
  • Peer Reviewed / Open Access
• [Journal Article] Peripheral blood monocyte count reflecting tumor-infiltrating macrophages is a predictive factor of adverse pathology in radical prostatectomy specimens (2017)
  • Author(s): Hayashi T, Fujita K, Nojima S, Hayashi Y, Nakano K, Ishizuya Y, Wang C, Yamamoto Y, Kinouchi T, Matsuzaki K, Kawamura N, Jingushi K, Kawashima A, Nagahara A, Ujike T, Uemura M, Imamura R, Morii E, Nonomura N.
  • Journal Title: Prostate. Volume: 77 Pages: 1383-1388
  • DOI: 10.1002/pros.23398
  • Peer Reviewed
• [Journal Article] Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms (2017)
  • Author(s): Kondo H, Maksimova N, Otomo T*,Kato H, Imai A, Asano Y, Kobayashi K, Nojima S, Nakaya A, Hamada Y, Irahara K, Gurinova E, Sukhomyasova A, Nogovicina A, Savvina M, Yoshimori T, Ozono K Sakai N*
  • Journal Title: Hum Mol Genet. Volume: 26 Pages: 173-183
  • DOI: 10.1093/hmg/ddw377
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immunohistochemical analysis of the novel marginal-zone B-cell marker IRTA1 in malignant lymphoma. (2017)
  • Author(s): Ikeda JI, Kohara M, Tsuruta Y, Nojima S, Tahara S, Ohshima K, Kurashige M, Wada N, Morii E.
  • Journal Title: Hum Pathol. Volume: 59 Pages: 70-79
  • DOI: 10.1016/j.humpath.2016.09.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Characterizing Semaphorin-Mediated Immune Responses Using an Antigen-Presentation Assay. (2017)
  • Author(s): Nojima S, Kumanogoh A.
  • Journal Title: Methods Mol Biol. Volume: 1493 Pages: 379-391
  • DOI: 10.1007/978-1-4939-6448-2_27
• [Journal Article] Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer. (2017)
  • Author(s): Ohshima K, Nojima S, Tahara S, Kurashige M, Hori Y, Hagiwara K, Okuzaki D, Oki S, Wada N, Ikeda JI, Kanai Y, Morii E.
  • Journal Title: Sci Rep. Volume: 7 Pages: 45504-45504
  • DOI: 10.1038/srep45504
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Requirement of CXCL12-CXCR7 signaling for CD20- CD138- double-negative population in lymphoplasmacytic lymphoma. (2016)
  • Author(s): Wada N, Ikeda J, Nojima S, Tahara S, Ohshima K, Okuzaki D, Morii E.
  • Journal Title: Lab Invest Volume: 96 Pages: 517-25
  • DOI: 10.1038/labinvest.2016.28
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation. (2016)
  • Author(s): Morimoto K, Baba Y, Shinohara H, Kang S, Nojima S, Kimura T, Ito D, Yoshida Y, Maeda Y, Sarashina-Kida H, Nishide M, Hosokawa T, Kato Y, Hayama Y, Kinehara Y, Okuno T, Takamatsu H, Hirano T, Shima Y, Narazaki M, Kurosaki T, Toyofuku T, Kumanogoh A.
  • Journal Title: Sci. Rep. Volume: 6 Pages: 25738-25738
  • DOI: 10.1038/srep25738
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic significance of a component of the Hippo pathway, TAZ, in human uterine endometrioid adenocarcinoma. (2016)
  • Author(s): Zhan M, Ikeda JI, Wada N, Hori Y, Nojima S, Tahara SI, Ueda Y, Yoshino K, Kimura T, Morii E.
  • Journal Title: Oncol Lett. Volume: 11 Pages: 3611-3616
  • Peer Reviewed
• [Journal Article] Overexpression of glypican-1 implicates poor prognosis and their chemoresistance in oesophageal squamous cell carcinoma. (2016)
  • Author(s): Hara, H., Takahashi, T., Serada, S., Fujimoto, M., Ohkawara, T., Nakatsuka, R., Harada, E., Nishigaki, T., Takahashi, Y., Nojima, S., Miyazaki, Y., Makino, T., Kurokawa, Y., Yamasaki, M., Miyata, H., Nakajima, K., Takiguchi, S., Morii, E., Mori, M., Doki, Y., Naka, T.
  • Journal Title: Br J Cancer. Volume: 115 Pages: 66-75
  • DOI: 10.1038/bjc.2016.183
  • Peer Reviewed / Open Access
• [Journal Article] CKAP4 is a Dickkopf1 receptor and is involved in tumor progression (2016)
  • Author(s): Kimura, H., Fumoto, K., Shojima, K., Nojima, S., Osugi, Y., Tomihara, H., Eguchi, H., Shintani, Y., Endo, E., Inoue, M., Doki, Y., Okumura, M., Morii, E., and Kikuchi, A.
  • Journal Title: J Clin Invest. Volume: 126 Pages: 2689-2705
  • DOI: 10.1172/jci84658
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] S100A4 accelerates the proliferation and invasion of endometrioid carcinoma and is associated with the ‘MELF’ pattern. (2016)
  • Author(s): Tahara S, Nojima S, Ohshima K, Hori Y, Kurashige M, Wada N, Ikeda J, Morii E.
  • Journal Title: Cancer Sci. Volume: 109 Pages: 1345-1352
  • DOI: 10.1111/cas.12999
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased fucosylated PSA as a urinary marker for high Gleason score prostate cancer. (2016)
  • Author(s): Fujita K, Hayashi T, Matsuzaki K, Nakata W, Masuda M, Kawashima A, Ujike T, Nagahara A, Tsuchiya M, Kobayashi Y, Nojima S, Uemura M, Morii E, Miyoshi E, Nonomura N.
  • Journal Title: Oncotarget. Volume: 7 Pages: 56643-56649
  • DOI: 10.18632/oncotarget.10987
  • Peer Reviewed / Open Access
• [Journal Article] Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals (2016)
  • Author(s): Kimura T, Nada S, Takegahara N, OkunoT, NojimaS, Kang S, Ito D, Morimoto K, Morimoto K, Hosokawa T, Hayama Y, Mitsui Y, Sakurai N, Sarashina-Kida H, Nishide M, Maeda Y, Takamatsu H, Okuzaki D, Yamada M, Okada M, Kumanogoh A.
  • Journal Title: Nat Commun Volume: 7 Pages: 13130-13130
  • DOI: 10.1038/ncomms13130
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ID1 upregulation and FoxO3a downregulation by Epstein-Barr virus-encoded LMP1 in Hodgkin's lymphoma. (2016)
  • Author(s): Ikeda JI, Wada N, Nojima S, Tahara S, Tsuruta Y, Oya K, Morii E.
  • Journal Title: Mol Clin Oncol. Volume: 5 Pages: 562-566
  • Peer Reviewed
• [Journal Article] 1.Semaphorin 4D contributes to rheumatoid arthritis by inducing inflammatory cytokine production: Pathogenic and therapeutic implications (2015)
  • Author(s): Yoshida Y, Ogata A, Kang S, Ebina K, Shi K, Nojima S, Kimura T, Ito D, Morimoto K, Nishide M, Hosokawa T, Hirano T, Shima Y, Narazaki M, Tsuboi H, Saeki Y, Tomita T, Tanaka T, Kumanogoh A.
  • Journal Title: Arthritis Rheumatol. Volume: none Pages: 1481-1490
  • DOI: 10.1002/art.39086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Wnt5a-Ror2 axis promotes the signaling circuit between interleukin-12 and interferon-γ in colitis. (2015)
  • Author(s): Sato, A., Kayama, H., Shojima, K., Matsumoto, S., Koyama, H., Minami, Y., Nojima, S., Morii, E., Honda, H., Takeda, K., Kikuchi, A.
  • Journal Title: Scientific Rep. Volume: 5 Pages: 10536-10536
  • DOI: 10.1038/srep10536
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells. (2015)
  • Author(s): Ito D, Nojima S*, Nishide M, Okuno T, Takamatsu H, Kang S, Kimura T, Yoshida Y, Morimoto K, Maeda Y, Hosokawa T, Toyofuku T, Ohshima J, Kamimura D, Yamamoto M, Murakami M, Morii E, Rakugi H, Isaka Y, Kumanogoh A*. (* correspondence)
  • Journal Title: J Immunol Volume: 195 Pages: 934-43
  • DOI: 10.4049/jimmunol.1403038
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Anti-Cancer Effects of Nonequilibrium Atmospheric Pressure Plasma on Cancer-Initiating Cells in Human Endometrioid Adenocarcinoma Cells. (2015)
  • Author(s): Ikeda J, Tsuruta Y, Nojima S, Sakakita H, Hori M, Ikehara Y.
  • Journal Title: Plasma Processes and Polymers. Volume: 12 Pages: 1370-1376
  • DOI: 10.1002/ppap.201500097
  • Peer Reviewed / Acknowledgement Compliant