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

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 24117711
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2013: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2012: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: 炎症 / がん / S100タンパク質 / S100受容体 / 転移 / 受容体

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
  • NAID: 120005372648
  • 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
  • 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
  • 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
  • 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
  • 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
• [Journal Article] Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells (2013)
  • Author(s): Saito K and Sakaguchi M
  • Journal Title: Oncogene Volume: in press Issue: 10 Pages: 1274-1286
  • DOI: 10.1038/onc.2013.66
  • Peer Reviewed
• [Journal Article] Partial sensitization of human bladder cancer cells to a gene-therapeutic adenovirus carrying REIC/Dkk-3 by downregulation of BRPK/PINK1. (2012)
  • Author(s): Jin Y, Murata H, Sakaguchi M, Kataoka K, Watanabe M, Nasu Y, Kumon H
  • Journal Title: Huh NH. Oncol Rep. Volume: 27(3) Pages: 695-9
  • DOI: 10.3892/or.2011.1543
  • Peer Reviewed
• [Journal Article] Expression pattern of REIC/Dkk-3 in mouse squamous epithelia (2012)
  • Author(s): Kataoka K
  • Journal Title: Clin Exp Dermatol Volume: 37 Issue: 4 Pages: 428-431
  • DOI: 10.1111/j.1365-2230.2011.04301.x
  • Peer Reviewed
• [Journal Article] Preclinical Safety and Efficacy of in Situ REIC/Dkk-3 Gene Therapy for Prostate Cancer (2012)
  • Author(s): Kawauchi K
  • Journal Title: Acta Med Okayama Volume: 66 Pages: 7-16
  • Peer Reviewed
• [Journal Article] S100A7 promotes the migration and invasion of osteosarcoma cells via the receptor for advanced glycation end products (2012)
  • Author(s): Kataoka K
  • Journal Title: Oncol Lett Volume: 3 Pages: 1149-1153
  • Peer Reviewed
• [Journal Article] REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic agent for bladder cancer. (2012)
  • Author(s): Hirata et al.
  • Journal Title: Int J Oncol. Volume: 41 Issue: 2 Pages: 559-564
  • DOI: 10.3892/ijo.2012.1503
  • Peer Reviewed
• [Journal Article] Preclinical biodistribution and safety study of reduced expression in immortalized cells/Dickkopf-3-encoding adenoviral vector for prostate cancer gene therapy (2012)
  • Author(s): Sugimoto M., Watanabe M., Kaku H., Li SA., Noguchi H., Ueki H., Sakaguchi M., Huh NH., Nasu Y., Kumon H
  • Journal Title: Oncol Rep Volume: 28巻 Issue: 5 Pages: 1645-1652
  • DOI: 10.3892/or.2012.2001
  • 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
• [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
• [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
• [Presentation] DOCK7 is a critical regulator of the RAGE-Cdc42 signaling axis that induces formation of dendritic pseudopodia in human cancer cells (2012)
  • Author(s): 山本健一
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-11
• [Presentation] TRAF6 Ubiquitinates and Stabilizes PINK1 on Damaged Mitochondria Through Interaction with SARM1 (2012)
  • Author(s): 村田 等
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-11
• [Presentation] Identification of novel receptors for pro-inflammatory S100A8/A9 proteins and their roles inmelanoma metastasis (2012)
  • Author(s): 阪口政清
  • Organizer: IEIIS2012. Homeostatic Inflammation Symposium
  • Place of Presentation: 東京
  • Year and Date: 2012-10-23
• [Presentation] S100A8およびS100A9タンパク質の新規受容体の探索とそのがん進展における役割 (2012)
  • Author(s): 阪口政清
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] A Novel Tumor Suppressor, REIC/Dkk-3 Gene Identified by our in Vitro Transformation Model of Normal Human Fibroblasts Works as a Potent Therapeutic Anti-tumor Agent (2012)
  • Author(s): 阪口政清
  • Organizer: 2012 World Congress on In Vitro Biology
  • Place of Presentation: アメリカ、Bellevue
  • Year and Date: 2012-06-03
  • Invited
• [Presentation] 細胞内導入型RAGE阻害ペプチドの開発 (2012)
  • Author(s): 村田等
  • Organizer: 日本生物工学会西日本支部創立30周年記念シンポジウム・講演会
  • Place of Presentation: 岡山市
• [Patent(Industrial Property Rights)] アデノウイルスベクターをがん細胞に対して選択的に導入可能なポリペプチドおよび当該ポリペプチドを備えるアデノウイルスベクター (2012)
  • Inventor(s): 阪口政清、近藤英作、許南浩、手塚克成
  • Industrial Property Rights Holder: 阪口政清、近藤英作、許南浩、手塚克成
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-085969
  • Filing Date: 2012-04-04
• [Patent(Industrial Property Rights)] PINK1のユビキチンアッセイ及びスクリーニングへの利用 (2012)
  • Inventor(s): 村田 等、阪口政清、許南浩
  • Industrial Property Rights Holder: 村田 等、阪口政清、許南浩
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-165160
  • Filing Date: 2012-07-25
• [Patent(Industrial Property Rights)] ＮＰＴＮβとＳ１００Ａ８の結合の阻害を指標とする細胞増殖抑制剤のスクリーニング方法 (2012)
  • Inventor(s): 阪口政清、日比野利彦、山本真実、許南浩
  • Industrial Property Rights Holder: 阪口政清、日比野利彦、山本真実、許南浩
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-204279
  • Filing Date: 2012-09-18