Cytoglobin overexpression inhibits liver fibrosis and cancer development via anti-oxidant function

• 研究課題/領域番号: 19K08428
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 審査区分: 小区分53010:消化器内科学関連
• 研究機関: 大阪市立大学
• 研究代表者: LE THITHANHTHUY 大阪市立大学, 大学院医学研究科, 特任講師 (10572175)
• 研究期間 (年度): 2019-04-01 – 2022-03-31
• 研究課題ステータス: 完了 (2021年度)
• 配分額: 4,290千円 (直接経費: 3,300千円、間接経費: 990千円); 2021年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円); 2020年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円); 2019年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
• キーワード: Liver fibrosis / Hepatic stellate cells / Cytoglobin / Antioxidant / Anti-fibrosis / Liver cancer / Hepatosteatosis / cytoglobin / Fibrosis / Hepatocellular Carcinoma / Hepatic Stellate Cells

研究開始時の研究の概要

Using Cygb knock out (KO) mice we already found the negative correlation in which loss of Cygb promoted severe liver inflammation,fibrosis and cancer. We generated a new transgenic (TG) mouse, generation of human recombinant CYGB proteins.

研究成果の概要

チオアセトアミド（TAA）注射の10週間後、またはコリン欠乏アミノ酸（CDAA）の16週間の摂食後、これらのモデルはすべて、Cygb欠損マウスでは重度の肝障害と線維症を示しましたが、Cygb過剰発現マウスでは減弱した。培養HSCでは、6Hisタグ付き組換えヒトCYGB（His-CYGB）がクラスリン媒介経路を介してエンドサイトーシスされた。 His-CYGBはROS形成を著しく阻害し、I型コラーゲンα1の産生を抑制した。 静脈内His-CYGBは、TAAまたはDDCで治療したマウスの肝臓の炎症、線維症、および酸化的細胞損傷を有意に抑制した。

研究成果の学術的意義や社会的意義

抗線維化療法は、ヒトの慢性肝疾患において満たされていない医学的ニーズのままです。 現在、線維症の理解に大きな進歩があり、肝線維形成の根底にある複数のメカニズムが明らかにされていますが、特定の効果的な抗線維化療法はとらえどころのないままです。 損傷後の肝臓の修復は高度に調整された調整されたプロセスであり、線維症を抑制することで肝臓を健康な状態に戻すことができます。 価値のある治療法を見つけるためのこれらの取り組みにおいて、肝硬変および癌の発症におけるCYGBの保護的役割は有望なものとなる可能性があります。

研究成果

• [雑誌論文] Cytoglobin Attenuated Pancreatic Cancer Growth in vitro and in vivo via Scavenging Function for Reactive Oxygen Species (2022)
  • 著者名/発表者名: 3.Dinh VH*, Thuy LTT*, Hai H, Hieu VN, Kimura K, Oikawa D, Ikura Y, Ninh QD, Hoang TH, Sato-Matsubara M, Dong MP, Hanh NV, Uchida-Kobayashi S, Tokunaga F, Kubo S, Ohtani N, Yoishizato K, and Kawada N
  • 雑誌名: Oncogenesis 巻: 0-0 ページ: 0-0
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Cytoglobin expression in pericyte and its role in pancreatic cancer (2021)
  • 著者名/発表者名: 1.Thuy le TT, Hai H, Dinh VH, Ngo VH, Uchida-Kobayashi S, Kawada N
  • 雑誌名: Gastroenterology & Hepatology 巻: 10 (3) ページ: 354-362
  • 査読あり
• [雑誌論文] 6His-tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species (2021)
  • 著者名/発表者名: Ninh Quoc Dat, Le Thi Thanh Thuy, Vu Ngoc Hieu, Fuminori Tokunaga, Massimo Pinzani, and Norifumi Kawada
  • 雑誌名: Hepatology 巻: 0-0 号: 6 ページ: 0-0
  • DOI: 10.1002/hep.31752
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization (2020)
  • 著者名/発表者名: Odagiri Naoshi、Hai Hoang、Thuy Le Thi Thanh、Dong Minh Phuong、Suoh Maito、Kotani Kohei、Hagihara Atsushi、Uchida-Kobayashi Sawako、Tamori Akihiro、Enomoto Masaru、Kawada Norifumi
  • 雑誌名: Cancers 巻: 12 号: 8 ページ: 2045-2045
  • DOI: 10.3390/cancers12082045
  • NAID: 120006878376
  • 査読あり / オープンアクセス
• [雑誌論文] Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis. (2020)
  • 著者名/発表者名: 3.Cheng-Hao Tseng, Yao-Chun Hsu, Tzu-Haw Chen, Fanpu Ji, I-Sung Chen, Ying-Nan Tsai, Hoang Hai, Le Thi Thanh Thuy, Tetsuya Hosaka, Hitomi Sezaki, John A Borghi, Ramsey Cheung, Masaru Enomoto, Mindie H Nguyen
  • 雑誌名: Lancet Gastroenterol Hepatol 巻: 5 号: 12 ページ: 1039-1052
  • DOI: 10.1016/s2468-1253(20)30249-1
  • 査読あり / オープンアクセス
• [雑誌論文] The anti-oxidative role of cytoglobin in podocytes: implications for a role in chronic kidney disease (2020)
  • 著者名/発表者名: Elisa B. Randi, Vervaet Benjamin, Maria Tsachaki, Elena Porto, Stijn Vermeylen, Maja T. Lindenmeyer, Le Thi Thanh Thuy, Clemens D. Cohen, Olivier Devuyst, Andreas Kistler, Csaba Szabo, Norifumi Kawada, Thomas Hankeln, Alex Odermatt, Sylvia Dewilde, Roland H. Wenger, David Hoogewijs.
  • 雑誌名: Antioxid Redox Signal 巻: 7 号: 16 ページ: 1155-1171
  • DOI: 10.1089/ars.2019.7868
  • 査読あり / 国際共著
• [雑誌論文] Role of Cytoglobin, a Novel Radical Scavenger, in Stellate Cell Activation and Hepatic Fibrosis. (2020)
  • 著者名/発表者名: Le Thi Thanh Thuy, Hoang Hai, and Norifumi Kawada
  • 雑誌名: Clinical and Molecular Hepatology 巻: - 号: 3 ページ: 280-293
  • DOI: 10.3350/cmh.2020.0037
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] TGF-β-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis (2020)
  • 著者名/発表者名: Yoshinori Okina, Misako Sato-Matsubara, Tsutomu Matsubara, Atsuko Daikoku, Lisa Longato, Krista Rombouts, Le Thi Thanh Thuy, Hiroshi Ichikawa5, Yukiko Minamiyama6, Mitsutaka Kadota7, Hideki Fujii, Masaru Enomoto, Kazuo Ikeda, Katsutoshi Yoshizato, Massimo Pinzani, and Norifumi Kawada
  • 雑誌名: Journal of Hepatology 巻: - 号: 4 ページ: 882-895
  • DOI: 10.1016/j.jhep.2020.03.051
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma. (2020)
  • 著者名/発表者名: Dong MP, Enomoto M, Thuy LTT, Hai H, Hieu VN, Hoang DV, Iida-Ueno A, Odagiri N, Amano-Teranishi Y, Hagihara A, Fujii H, Uchida-Kobayashi S, Tamori A, Kawada N.
  • 雑誌名: Sci Rep 巻: 10 号: 1 ページ: 3392-3392
  • DOI: 10.1038/s41598-020-60440-5
  • 査読あり / オープンアクセス / 国際共著
• [学会発表] Levels of soluble immune checkpoint proteins following antiviral treatment in chronic hepatitis C patients and the roles of sCD27 in hepatocellular carcinoma development (2021)
  • 著者名/発表者名: Minh Phuong Dong, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Dinh Viet Hoang, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori and Norifumi Kawada
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Investigation of CYGB promoter methylation in hepatocellular carcinoma (2021)
  • 著者名/発表者名: Hoang Hai, Le Thi Thanh Thuy, Akihiro Tamori, Shoji Kubo, Shigekazu Takemura, Shogo Tanaka, Atsushi Hagihara, Etsushi Kawamura, Sawako Uchida-Kobayashi, Masaru Enomoto and Norifumi Kawada
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Anti-fibrotic Capacity of Extracellular Globins via Scavenging ROS and Promoting MMP-1 Secretion (2021)
  • 著者名/発表者名: Vu Ngoc Hieu, Le Thi Thanh Thuy, Ninh Quoc Dat, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoshizato and Norifumi Kawada
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Organize Committee, Scientific secretary (2021)
  • 著者名/発表者名: Le Thi Thanh Thuy
  • 学会等名: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC) on “Molecular and Cell Biology of the Liver: Recent Evolution to Clinical Application” in Osaka
  • 国際学会
• [学会発表] Capacity of Extracellular Globins in suppression of Collagen Production from activated Hepatic Stellate cells via Scavenging ROS and Promoting MMP-1 Secretion (2021)
  • 著者名/発表者名: Vu Ngoc Hieu, Le Thi Thanh Thuy, Ninh Quoc Dat, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoshizato and Norifumi Kawada
  • 学会等名: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC)
  • 国際学会
• [学会発表] Changes of soluble immune checkpoint proteins following antiviral treatment in chronic hepatitis C patients and the roles of the CD27-CD70 pathway in hepatocellular carcinoma development (2021)
  • 著者名/発表者名: Minh Phuong Dong, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Dinh Viet Hoang, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori and Norifumi Kawada
  • 学会等名: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC)
  • 国際学会
• [学会発表] Role of CD40 in Hepatocellular Carcinoma (2021)
  • 著者名/発表者名: Ngo Vinh Hanh, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori, and Norifumi Kawada
  • 学会等名: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC)
  • 国際学会
• [学会発表] Cytoglobin impairs pancreatic cancer growth in vitro and in vivo (2021)
  • 著者名/発表者名: Dinh Viet Hoang, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Ninh Quoc Dat, Truong Huu Hoang, Dong Minh Phuong, Ngo Vinh Hanh, Yoshihiro Ikura, Kenjiro Kimura, and Norifumi Kawada
  • 学会等名: Annual Meeting of the Digestive Disease Week (DDW)
  • 国際学会
• [学会発表] Interaction between CD4+T cells and tumor cells in hepatocellular carcinoma microenvironment (2021)
  • 著者名/発表者名: Ngo Vinh Hanh, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori, and Norifumi Kawada
  • 学会等名: Annual Meetings for Hepatic Sinusoidal Research Japan
• [学会発表] Novel Anti-Fibrotic Function of Neuroglobin in vitro and in vivo (2021)
  • 著者名/発表者名: Vu Ngoc Hieu, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Ninh Quoc Dat, Katsutoshi Yoishizato and Norifumi Kawada
  • 学会等名: Annual Meetings for Hepatic Sinusoidal Research Japan
• [学会発表] Anti-fibrosis application of overexpression and recombinant human CYGB in multiple models of advanced fibrosis (2021)
  • 著者名/発表者名: Le Thi Thanh Thuy, Ninh Quoc Dat, Vu Ngoc Hieu, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada
  • 学会等名: 29th Japan Gastroenterological Society Week
• [学会発表] Circulating soluble immune checkpoint proteins as biomarkers for predicting the outcome of antiviral treatment of chronic hepatitis B (2021)
  • 著者名/発表者名: Hoang Hai, Masaru Enomoto, Minh Phuong Dong, Le Thi Thanh Thuy, Atsushi Hagihara, Sawako Uchida-Kobayashi, Akihiro Tamori, and Norifumi Kawada
  • 学会等名: 29th Japan Gastroenterological Society Week
• [学会発表] Level of soluble immune checkpoint proteins associate with hepatocellular carcinoma development in patients with chronic hepatitis C (2021)
  • 著者名/発表者名: Dong Minh Phuong, Le Thi Thanh Thuy, Hoang Hai, Akihiro Tamori, Masaru Enomoto, Sawako Uchida-Kobayashi and Norifumi Kawada
  • 学会等名: The 57th Annual Meeting of the Japan Society of Hepatology
• [学会発表] Recombinant human Cytoglobin Deactivates Hepatic Stellate Cells and Prevents Fibrosis Aggravation by Scavenging ROS and Inducing Interferon-Beta (2021)
  • 著者名/発表者名: Vu Ngoc Hieu, Ninh Quoc Dat, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada
  • 学会等名: The 107th General Meeting of the Japanese Society of Gastroenterology
• [学会発表] Cytoglobin inhibits pancreatic cancer growth in vitro and in vivo (2021)
  • 著者名/発表者名: Dinh Viet Hoang, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Ninh Quoc Dat, Truong Huu Hoang, Dong Minh Phuong, Ngo Vinh Hanh, Yoshihiro Ikura, Kenjiro Kimura, and Norifumi Kawada
  • 学会等名: The 107th General Meeting of the Japanese Society of Gastroenterology
• [学会発表] Hepatocellular carcinoma incidence with tenofovir vs entecavir in chronic hepatitis b: a systematic review and meta-analysis (2020)
  • 著者名/発表者名: Tseng, CH; Hsu, YC; Chen, TH; Ji, FP; Chen, IS; Tsai, YN; Hai, H; Le Thuy, TT; Hosaka, T; Sezaki, H; Borghi, JA; Cheung, R; Enomoto, M; Nguyen, MH.
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Early change in the plasma levels of circulating soluble immune checkpoint proteins in patients with unresectable hepatocellular carcinoma treated by lenvatinib or transcatheter arterial chemoembolization. (2020)
  • 著者名/発表者名: Odagiri N, Enomoto M, Hai H, Le Thuy TT, Dong MP, Suoh M, Kotani K, Hagihara A, Uchida S, Tamori A, Kawada N.
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Recombinant human Cytoglobin scavenging ROS and inducing Interferon-Beta mediated hepatic stellate cells activation and liver fibrosis (2020)
  • 著者名/発表者名: Vu Ngoc Hieu, Ninh Quoc Dat, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada
  • 学会等名: 56th Annual Meeting of Japanese Society of Hepatology
• [学会発表] Recombinant human Cytoglobin Deactivates Hepatic Stellate Cells and Prevents Fibrosis Aggravation by Scavenging ROS and Inducing Interferon-Beta (2020)
  • 著者名/発表者名: 1.Vu Ngoc Hieu, Ninh Quoc Dat, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada.
  • 学会等名: Symposium oral presentation at the 107th General Meeting of the Japanese Society of Gastroenterology
• [学会発表] Cytoglobin inhibits pancreatic cancer growth in vitro and in vivo (2020)
  • 著者名/発表者名: 2.Dinh Viet Hoang, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Ninh Quoc Dat, Truong Huu Hoang, Dong Minh Phuong, Ngo Vinh Hanh, Yoshihiro Ikura, Kenjiro Kimura, and Norifumi Kawada
  • 学会等名: 107th General Meeting of the Japanese Society of Gastroenterology
• [学会発表] Loss of Cytoglobin linked to specific gut microbiota patterns drives intrahepatic bile duct hyperplasia and reduces survival rate in mice feeding CDAA diet and deoxycholic acid. (2019)
  • 著者名/発表者名: Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Vu Ngoc Hieu, Katsutoshi Yoishizato, and Norifumi Kawada.
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Cytoglobin protects mice from hepatic fibrosis and cancer induced by different aetiologies via scavenging reactive oxygen species (2019)
  • 著者名/発表者名: Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Vu Ngoc Hieu, Ninh Quoc Dat, Katsutoshi Yoishizato, and Norifumi Kawada.
  • 学会等名: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • 国際学会
• [学会発表] Cytoglobin suppresses liver fibrosis and cancer in mice by regulating oxidative stress (2019)
  • 著者名/発表者名: Le Thi Thanh Thuy, Ninh Quoc Dat, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato, and Norifumi Kawada
  • 学会等名: 55th Annual Meeting of Japanese Society of Hepatology
• [学会発表] The way to the science of a Vietnamese doctor (2019)
  • 著者名/発表者名: Le Thi Thanh Thuy
  • 学会等名: the 43rd Meeting of Western Branch of The Japan Society of Hepatology
  • 招待講演
• [学会発表] Chairman for the session of Biology and Medicine (2019)
  • 著者名/発表者名: Le Thi Thanh Thuy
  • 学会等名: Vietnam-Japan Science and Technology Symposium
  • 国際学会 / 招待講演
• [図書] The Evolving Landscape of Liver Cirrhosis Management. Chapter 16: Antifibrotic therapy for liver cirrhosis. (2019)
  • 著者名/発表者名: Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Ninh Quoc Dat, Dinh Viet Hoang, and Norifumi Kawada.
  • 出版者: Springer Nature Singapore Pte Ltd
  • ISBN: 9789811379796
• [産業財産権] 肝星細胞の活性化並びに肝炎;肝線維化を抑制するサイトグロビン関連ペプチド (2019)
  • 発明者名: 河田 則文, LE THI THANH THUY
  • 権利者名: 河田 則文, LE THI THANH THUY
  • 産業財産権種類: 特許
  • 出願年月日: 2019
  • 取得年月日: 2021
• [産業財産権] 肝星細胞の活性化並びに肝炎・肝線維化を抑制するサイトグロビン関連ペプチド (2019)
  • 発明者名: 河田 則文, LE THI THANH THUY
  • 権利者名: 河田 則文, LE THI THANH THUY
  • 産業財産権種類: 特許
  • 出願年月日: 2019