Elucidation of the mechanism of cell membrane dynamics and cancer malignant signaling through RAGE transmembrane domain

• Project/Area Number: 20K07323
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Kanazawa University
• Principal Investigator: Munesue Seiichi 金沢大学, 医学系, 助教 (10399040)
• Co-Investigator(Kenkyū-buntansha): 木村 久美 金沢大学, 医学系, 助教 (60409472)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: RAGE / がん悪性化 / 細胞膜ダイナミクス / 膜ダイナミクス

Outline of Research at the Start

研究代表者らは、骨肉腫細胞が悪性化し、がん幹細胞様のスフェロイド形成の誘導を示す現象が、パターン認識受容体として知られているRAGEの細胞膜領域の存在のみで成立することを見出した。この現象の機構を明らかにするために、本研究ではRAGE細胞膜領域により誘導される細胞膜ダイナミクイスの変化を明らかにするため、RAGE細胞膜領域結合タンパク質、およびRAGE細胞膜領域により変化する脂質ラフト局在タンパク質の探索を試みる。また、高速原子間力顕微鏡を用いてRAGE細胞膜領域による細胞膜ダイナミクス変化の視覚化の可能性を探る。

Outline of Final Research Achievements

The expression of RAGE (receptor for advanced glycation end-products), known as a pattern recognition receptor, is essential for the spheroid formation of human osteosarcoma cells (HOS). In this study, the purpose of this research application was to clarify the intracellular signal for spheroid formation. As a result, we demonstrated that TM (RAGE) localizes to lipid rafts, which are functional domains on the cell membrane, and that the spheroid formation is specific to TM (RAGE). Furthermore, we identified a TM(RAGE)-binding protein X and clarified that protein X is an essential molecule for spheroid formation.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、悪性化骨肉腫細胞が培養下で形成するスフェロイドの形成機構の分子メカニズムの一端を明らかにするものであり、本研究成果に基づいて新たな悪性がんの治療戦略の創出の基礎を生み出そうとするものであり学術的な意義は大きい。
また、日本の死因の第一位はがんであり、がんの治療戦略の創出に関わる研究成果の社会的意義は大きい。

Research Products

• [Journal Article] Oxytocin Dynamics in the Body and Brain Regulated by the Receptor for Advanced Glycation End-Products, CD38, CD157, and Nicotinamide Riboside (2022)
  • Author(s): H. Higashida, K. Furuhara, O. Lopatina, M. Gerasimenko, O. Hori, T. Hattori, Y. Hayashi, S. M. Cherepanov, A. A. Shabalova, A. B. Salmina, K. Minami, T. Yuhi, C. Tsuji, P. Y. Fu, Z. Liu, S. Luo, A. Zhang, S. Yokoyama, S. Shuto, M. Watanabe, K. Fujiwara, S. Munesue, A. Harashima, Y. Yamamoto
  • Journal Title: Frontiers in Neuroscience Volume: 16 Pages: 858070-858070
  • DOI: 10.3389/fnins.2022.858070
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation (2022)
  • Author(s): Hayashi Kenjiro、Sato Koichi、Ochi Seishi、Kawano Shuhei、Munesue Seiichi、Harashima Ai、Oshima Yu、Kimura Kumi、Kyoi Takashi、Yamamoto Yasuhiko
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 10 Pages: 5757-5757
  • DOI: 10.3390/ijms23105757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Use of Cocultures to Measure the Blood-Brain Barrier Permeability of Oxytocin. (2022)
  • Author(s): Yamamoto Y, Harashima A, Munesue SI, Higashida H.
  • Journal Title: Methods Mol Biol. Volume: 2384 Pages: 247-255
  • DOI: 10.1007/978-1-0716-1759-5_15
  • ISBN: 9781071617588, 9781071617595
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dual Nature of RAGE in Host Reaction and Nurturing the Mother-Infant Bond. (2022)
  • Author(s): Oshima Y, Harashima A, Munesue S, Kimura K, Leerach N, Goto H, Tanaka M, Niimura A, Hayashi K, Yamamoto H, Higashida H, Yamamoto Y.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 4 Pages: 2086-2086
  • DOI: 10.3390/ijms23042086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis (2022)
  • Author(s): Takei R, Miyashita T, Takada S, Tajima H, Ninomiya I, Takamura H, Fushida S, Harashima A, Munesue S, Yagi S, Inaki N, Ohta T, Yamamoto Y.
  • Journal Title: Cancer Immunol Immunother. Volume: 71 Issue: 4 Pages: 777-789
  • DOI: 10.1007/s00262-021-03027-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury (2022)
  • Author(s): Miyagawa Taro、Iwata Yasunori、Oshima Megumi、Ogura Hisayuki、Sato Koichi、Nakagawa Shiori、Yamamura Yuta、Kamikawa Yasutaka、Miyake Taito、Kitajima Shinji、Toyama Tadashi、Hara Akinori、Sakai Norihiko、Shimizu Miho、Furuichi Kengo、Munesue Seiichi、Yamamoto Yasuhiko、Kaneko Shuichi、Wada Takashi
  • Journal Title: Biology Open Volume: 11 Issue: 1 Pages: 1-8
  • DOI: 10.1242/bio.058852
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correction to: Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis. (2022)
  • Author(s): Takei R, Miyashita T, Takada S, Tajima H, Ninomiya I, Takamura H, Fushida S, Harashima A, Munesue S, Yagi S, Inaki N, Ohta T, Yamamoto Y.
  • Journal Title: Cancer Immunol Immunother. Volume: 71 Issue: 4 Pages: 791-793
  • DOI: 10.1007/s00262-021-03039-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thrombopoietin accumulation in hepatocytes induces a decrease in its serum levels in a sinusoidal obstruction syndrome model. (2022)
  • Author(s): Yamazaki H, Tajima H, Yamamoto Y, Munesue S, Okazaki M, Ohbatake Y, Nakanuma S, Makino I, Miyashita T, Takamura H, Ohta T.
  • Journal Title: Mol Med Rep. Volume: 25 Issue: 6 Pages: 201-201
  • DOI: 10.3892/mmr.2022.12717
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Receptor for advanced glycation end-products (RAGE) plays a critical role in retrieval behavior of mother mice at early postpartum. (2021)
  • Author(s): Gerasimenko M, Lopatina O, Munesue S, Harashima A, Yokoyama S, Yamamoto Y, Higashida H.
  • Journal Title: Physiol Behav Volume: 235 Pages: 113395-113395
  • DOI: 10.1016/j.physbeh.2021.113395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transport of oxytocin to the brain after peripheral administration by membrane‐bound or soluble forms of receptors for advanced glycation end‐products. (2021)
  • Author(s): Munesue S, Liang M, Harashima A, Zhong J, Furuhara K, Boitsova BE, Cherepanov MS, Gerasimenko M, Yuhi T, Yamamoto Y, Higashida H.
  • Journal Title: J Neuroendocrinol. Volume: in press Pages: 0-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RAGE signaling antagonist suppresses mouse macrophage foam cell formation. (2021)
  • Author(s): Leerach N, Munesue S, Harashima A, Kimura K, Oshima Y, Kawano S, Tanaka M, Nimura A, Sakulsak N, Yamamoto H, Hori O, Yamamoto Y
  • Journal Title: Biochem Biophys Res Commun. Volume: in press Pages: 0-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glycation reaction and the role of the receptor for advanced glycation end-products in immunity and social behavior. (2020)
  • Author(s): Leerach N, Harashima A, Munesue S, Kimura K, Oshima Y, Goto H, Yamamoto H, Higashida H, Yamamoto Y.
  • Journal Title: Glycoconj J. Volume: in press Pages: 0-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroprotective Effects of Endogenous Secretory Receptor for Advanced Glycation End-products in Brain Ischemia. (2020)
  • Author(s): Shimizu Y, Harashima A, Munesue S, Oishi M, Hattori T, Hori O, Kitao Y, Yamamoto H, Leerach N, Nakada M, Yamamoto Y, Hayashi Y.
  • Journal Title: Aging Dis. Volume: 11 Pages: 547-558
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aquaporin 1 elicits cell motility and coordinates vascular bed formation by downregulating thrombospondin type-1 domain-containing 7A in glioblastoma. (2020)
  • Author(s): Oishi M, Munesue S, Harashima A, Nakada M, Yamamoto Y, Hayashi Y. Aquaporin 1 elicits cell motility and coordinates vascular bed formation by downregulating thrombospondin type-1 domain-containing 7A in glioblastoma.
  • Journal Title: Cancer Med. Volume: 9 Pages: 3904-3917
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Analyzing molecular basis of cancer malignancy and RAGE (2022)
  • Author(s): Seiichi MUNESUE, Akihiko TAKEUCHI, Ai HARASHIMA, Kumi KIMURA, Yu Oshima, Mariko TANAKA, Yasuhiko YAMAMOTO
  • Organizer: 日本メイラード学会
• [Presentation] グリケーションとその最終産物受容体RAGE ― 病態形成における意義について ― (2021)
  • Author(s): 棟居聖一、山本靖彦
  • Organizer: 第94回日本生化学会大会
• [Presentation] RAGE細胞内シグナル伝達阻害によるマクロファージ泡沫化抑制効果 (2021)
  • Author(s): 原島 愛、Nontaphat Leerach、棟居聖一、木村久美、大島 由、 林 謙次郎、後藤久典、田中麻莉子、新村朱子、橋本 篤、山本靖彦
  • Organizer: 腎とフリーラジカル研究会
• [Presentation] 原子間力顕微鏡によるタンパク質グリケーションの可視化 (2021)
  • Author(s): 新村朱子、木下結衣、原島 愛、棟居聖一、木村久美、Nontaphat Leerach、 大島 由、林 謙次郎、田中麻莉子、後藤久典、古寺哲幸、山本靖彦
  • Organizer: 第30回日本メイラード学会年会
• [Presentation] 内在性分泌型 RAGE が血中オキシトシンの脳内輸送に与える影響の検討 (2021)
  • Author(s): 原島 愛、棟居聖一、木村久美 、Nontaphat Leerach、大島 由、 林謙次郎、新村朱子、田中麻莉子、東田陽博、山本靖彦
  • Organizer: 日本生化学会北陸支部第39回大会
• [Presentation] がんの腫瘍悪性形質はRAGEによって制御される (2021)
  • Author(s): 棟居聖一、武内章彦、原島愛、木村久美、Nontaphat Leerach、 大島 由、田中麻莉子、新村朱子、山本 博、山本靖彦
  • Organizer: 日本生化学会北陸支部第39回大会
• [Presentation] 食後誘導される末梢血好中球NETosisとその意義について (2021)
  • Author(s): 大島 由、田中麻莉子、Nontaphat Leerach、林謙次郎、 新村朱子、棟居聖一、原島 愛、木村久美、山本靖彦
  • Organizer: 日本生化学会北陸支部第39回大会
• [Presentation] 可溶型RAGEは脳血管内皮細胞上の膜型RAGEによる血中オキシトシンの脳内輸送を阻害しない (2020)
  • Author(s): 棟居聖一、原島愛、木村久美、Nontaphat Leerach、大島由、新村朱子、東田陽博、山本靖彦
  • Organizer: 第30回日本メイラード学会（オンライン）
• [Book] 糖化ストレス (2020)
  • Author(s): 棟居聖一、山本靖彦
  • Total Pages: 379
  • Publisher: シーエムシー出版
• [Remarks] 金沢大学大学院・医薬保健研究域・医学系・血管分子生物学
  • URL: https://biochem2.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学大学院・医薬保健学総合研究科・医学専攻・血管分子生物学
  • URL: https://biochem2.w3.kanazawa-u.ac.jp/