炎症を感知する新規内因性リガンドセンサーの作動機構解明とがん進展における役割

2013 Fiscal Year Annual Research Report

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 24117711
• Research Institution: Okayama University
• Principal Investigator: 阪口 政清 岡山大学, 医歯(薬)学総合研究科, 准教授 (70379840)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 炎症 / がん / S100タンパク質 / S100受容体 / 転移

Research Abstract

S100A8/A9結合タンパク質の解析から新規受容体としてEMMPRINとR8（仮称）を見出すことに成功した。R8には、二つのスプライシングバリアント、αとβが存在した。EMMPRINとR8αはS100A9に、R8βはS100A8とS100A9に親和性を示した。これら受容体の下流信号伝達の解析から、全て(EMMPRIN, R8α, R8β)に共通してアダプタータンパク質群TRAF2を同定することにも成功した。全ての受容体の下流で、TRAF2はRac/Cdc42を介して細胞の走化性を上昇させる機能を持っていた。メラノーマ塊の組織染色の結果、メラノーマには、同定できた全て(EMMPRIN, R8α, R8β)の受容体が発現していた。興味深い事に、腫瘍周囲の正常組織ではS00A8/A9の発現が顕著であり、それに接しているメラノーマに受容体群の発現が特に顕著であった。移植実験を行ったところ、メラノーマでは、３種の受容体の中でも特にEMMPRINの機能抑制が、肺（S100A8/A9存在）へのメラノーマ転移の顕著な抑制につながることが判明した（EMMPRINは遠隔転移に関わる）。現在の研究からR8α, R8βは、周囲の正常組織からのS100A8/A9を受け、腫瘍塊増殖進展に関わっている事を示唆するデータが出つつあり、その詳細について検討を進めている。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Preclinical Evaluation of MicroRNA-34b/c Delivery for Malignant Pleural Mesothelioma (2014)
  • Author(s): Ueno T, Toyooka S, Fukazawa T, Kubo T, Soh J, Asano H, Muraoka T, Tanaka N, Maki Y, Shien K, Furukawa M, Sakaguchi M, Yamamoto H, Tsukuda K, Miyoshi S
  • Journal Title: Acta Med Okayama Volume: 68 Pages: 23-26
  • Peer Reviewed
• [Journal Article] Dramatic increase in expression of a transgene by insertion of promoters downstream of the cargo gene (2014)
  • Author(s): Sakaguchi M, Watabe M, Kinoshita R, Kaku H, Ueki H, Futami J, Murata H, Inoue Y, Li SA, Huang P, Putranto EW, Ruma IMW, Nasu Y, Kumon H, Huh NH
  • Journal Title: Mol Biotech Volume: In press Pages: In press
  • Peer Reviewed
• [Journal Article] Anti-Cancer Effects of REIC/Dkk-3-encoding Adenoviral Vector for the Treatment of Non-small Cell Lung Cancer (2014)
  • Author(s): Shien K, Tanaka N, Watanabe M, Soh J, Sakaguchi M, Matsuo K, Yamamoto H, Furukawa M, Asano H, Tsukuda K, Nasu Y, Huh NH, Miyoshi S, Kumon H, Toyooka S
  • Journal Title: PLoS One Volume: 9 Pages: e87900
  • Peer Reviewed
• [Journal Article] Draft Genome Sequence of Clostridium botulinum Type B Strain Osaka05, Isolated from an Infant Patient with Botulism in Japan (2014)
  • Author(s): Sakaguchi Y, Hosomi K, Uchiyama J, Ogura Y, Umeda K, Sakaguchi M, Kohda T, Mukamoto M, Misawa N, Matsuzaki S, Hayashi T, Kozaki S
  • Journal Title: Genome Announc Volume: 2 Pages: pii: e01010-13
  • Peer Reviewed
• [Journal Article] A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector (2014)
  • Author(s): Watanabe M, Sakaguchi M, Kinoshita R, Kaku H, Ariyoshi Y, Ueki H, Tanimoto R, Ebara S, Ochiai K, Futami J, Li SA, Huang P, Nasu Y, Huh NH, Kumon H
  • Journal Title: Oncol Rep Volume: 31 Pages: 1089-1095
  • Peer Reviewed
• [Journal Article] Novel germ-line mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas (2014)
  • Author(s): Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J, Ichimura K, Furukawa M, Hashida S, Tsukuda K, Takigawa N, Matsuo K, Kiura K, Miyoshi S, Matsuda F, Toyooka S
  • Journal Title: J Natl Cancer Inst Volume: 106 Pages: djt338
  • Peer Reviewed
• [Journal Article] Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells (2014)
  • Author(s): Saito K, Sakaguchi M, Iioka H, Matsui M, Nakanishi H, Huh NH, Kondo E
  • Journal Title: Oncogene Volume: 33 Pages: 1274-1286
  • Peer Reviewed
• [Journal Article] SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria (2014)
  • Author(s): Murata H, Sakaguchi M, Kataoka K, Huh NH
  • Journal Title: Mol Biol Cell Volume: 24 Pages: 2772-2784
  • Peer Reviewed
• [Journal Article] S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis (2013)
  • Author(s): Hibino T, Sakaguchi M, Miyamoto S, Yamamoto M, Motoyama A, Hosoi J, Shimokata T, Ito T, Tsuboi R, Huh NH
  • Journal Title: Cancer Res Volume: 73 Pages: 172-183
  • Peer Reviewed
• [Journal Article] Inhibition of RAGE signaling by intracellular delivered-inhibitor peptides using PEI-cationization (2013)
  • Author(s): Putranto EW, Murata H, Yamamoto K, Kataoka K, Yamada H, Futami J, Sakaguchi M, Huh NH
  • Journal Title: Int J Mol Med Volume: 32 Pages: 938-944
  • Peer Reviewed
• [Journal Article] DOCK7 is a critical regulator of the RAGE-Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells (2013)
  • Author(s): Yamamoto K, Murata H, Putranto EW, Kataoka K, Motoyama A, Hibino T, Inoue Y, Sakaguchi M, Huh NH
  • Journal Title: Oncol Rep Volume: 29 Pages: 1073-1079
  • Peer Reviewed
• [Presentation] Identification of RAGE-coupled receptor that modulates RAGE-triggered signaling pathway (2013)
  • Author(s): Masakiyo Sakaguchi, Hitoshi Murata, Toshihiko Hibino, Yumi Aoyama, Keiji Iwatsuki, Nam-ho Huh
  • Organizer: The American Society for Cell Biology (ASCB) annual meeting
  • Place of Presentation: New Orleans, LA, USA
  • Year and Date: 20131214-20131218
• [Presentation] S100A8/A9 targets oncogenic survival pathway via RAGE that critically enhanced by a RAGE co-receptor(多機能受容体RAGEの共役受容体の発見とその意義) (2013)
  • Author(s): Masakiyo Sakaguchi, Hitoshi Murata, Toshihiko Hibino, and Nam-ho Huh
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 20131003-20131005
• [Presentation] 多機能受容体RAGEの共役受容体の発見とその意義 (2013)
  • Author(s): 阪口 政清
  • Organizer: 新学術領域「自然炎症」「脂質マシナリ」合同若手ワークショップ
  • Place of Presentation: 鳴門市
  • Year and Date: 20130702-20130704