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

• Project/Area Number: 19K08428
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Osaka City University
• Principal Investigator: Le Thi Thanh Thuy 大阪市立大学, 大学院医学研究科, 特任講師 (10572175)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Liver fibrosis / Hepatic stellate cells / Cytoglobin / Antioxidant / Anti-fibrosis / Liver cancer / Hepatosteatosis / cytoglobin / Fibrosis / Hepatocellular Carcinoma / Hepatic Stellate Cells

Outline of Research at the Start

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.

Outline of Final Research Achievements

We have investigated the role of endogenous CYGB on liver diseases using CYGB deficient (Cygb-KO) mice and CYGB transgenic (Cygb-TG) mice under 10 weeks after thioacetamide (TAA) injection, or 16 weeks of choline deficient amino acid define diet (CDAA) feeding. These all models showed that absence of Cygb significantly exacerbated liver damage, fibrosis and reactive oxygen species (ROS) formation which were attenuated in Cygb-overexpressing mice. We have produced 6His-tagged recombinant human CYGB (His-CYGB). In cultured HSCs, His-CYGB was endocytosed and accumulated in endosomes via clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type I alpha 1 production and alpha-smooth muscle actin expression. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis and oxidative cell damage in TAA- or DDC-administered mice without adverse effects.

Academic Significance and Societal Importance of the Research Achievements

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。

Research Products

• [Journal Article] Cytoglobin Attenuated Pancreatic Cancer Growth in vitro and in vivo via Scavenging Function for Reactive Oxygen Species (2022)
  • Author(s): 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
  • Journal Title: Oncogenesis Volume: 0-0 Pages: 0-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cytoglobin expression in pericyte and its role in pancreatic cancer (2021)
  • Author(s): 1.Thuy le TT, Hai H, Dinh VH, Ngo VH, Uchida-Kobayashi S, Kawada N
  • Journal Title: Gastroenterology & Hepatology Volume: 10 (3) Pages: 354-362
  • Peer Reviewed
• [Journal Article] 6His-tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species (2021)
  • Author(s): Ninh Quoc Dat, Le Thi Thanh Thuy, Vu Ngoc Hieu, Fuminori Tokunaga, Massimo Pinzani, and Norifumi Kawada
  • Journal Title: Hepatology Volume: 0-0 Issue: 6 Pages: 0-0
  • DOI: 10.1002/hep.31752
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Cancers Volume: 12 Issue: 8 Pages: 2045-2045
  • DOI: 10.3390/cancers12082045
  • NAID: 120006878376
  • Peer Reviewed / Open Access
• [Journal Article] Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis. (2020)
  • Author(s): 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
  • Journal Title: Lancet Gastroenterol Hepatol Volume: 5 Issue: 12 Pages: 1039-1052
  • DOI: 10.1016/s2468-1253(20)30249-1
  • Peer Reviewed / Open Access
• [Journal Article] The anti-oxidative role of cytoglobin in podocytes: implications for a role in chronic kidney disease (2020)
  • Author(s): 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.
  • Journal Title: Antioxid Redox Signal Volume: 7 Issue: 16 Pages: 1155-1171
  • DOI: 10.1089/ars.2019.7868
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of Cytoglobin, a Novel Radical Scavenger, in Stellate Cell Activation and Hepatic Fibrosis. (2020)
  • Author(s): Le Thi Thanh Thuy, Hoang Hai, and Norifumi Kawada
  • Journal Title: Clinical and Molecular Hepatology Volume: - Issue: 3 Pages: 280-293
  • DOI: 10.3350/cmh.2020.0037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TGF-β-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis (2020)
  • Author(s): 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
  • Journal Title: Journal of Hepatology Volume: - Issue: 4 Pages: 882-895
  • DOI: 10.1016/j.jhep.2020.03.051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma. (2020)
  • Author(s): 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.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 3392-3392
  • DOI: 10.1038/s41598-020-60440-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Levels of soluble immune checkpoint proteins following antiviral treatment in chronic hepatitis C patients and the roles of sCD27 in hepatocellular carcinoma development (2021)
  • Author(s): 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
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Investigation of CYGB promoter methylation in hepatocellular carcinoma (2021)
  • Author(s): 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
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Anti-fibrotic Capacity of Extracellular Globins via Scavenging ROS and Promoting MMP-1 Secretion (2021)
  • Author(s): Vu Ngoc Hieu, Le Thi Thanh Thuy, Ninh Quoc Dat, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoshizato and Norifumi Kawada
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Organize Committee, Scientific secretary (2021)
  • Author(s): Le Thi Thanh Thuy
  • Organizer: 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
  • Int'l Joint Research
• [Presentation] Capacity of Extracellular Globins in suppression of Collagen Production from activated Hepatic Stellate cells via Scavenging ROS and Promoting MMP-1 Secretion (2021)
  • Author(s): Vu Ngoc Hieu, Le Thi Thanh Thuy, Ninh Quoc Dat, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoshizato and Norifumi Kawada
  • Organizer: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC)
  • Int'l Joint Research
• [Presentation] 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)
  • Author(s): 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
  • Organizer: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC)
  • Int'l Joint Research
• [Presentation] Role of CD40 in Hepatocellular Carcinoma (2021)
  • Author(s): Ngo Vinh Hanh, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori, and Norifumi Kawada
  • Organizer: The Asian Pacific Association for the Study of the Liver Single Topic Conference (APASL STC)
  • Int'l Joint Research
• [Presentation] Cytoglobin impairs pancreatic cancer growth in vitro and in vivo (2021)
  • Author(s): 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
  • Organizer: Annual Meeting of the Digestive Disease Week (DDW)
  • Int'l Joint Research
• [Presentation] Interaction between CD4+T cells and tumor cells in hepatocellular carcinoma microenvironment (2021)
  • Author(s): Ngo Vinh Hanh, Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Sawako Uchida-Kobayashi, Masaru Enomoto, Akihiro Tamori, and Norifumi Kawada
  • Organizer: Annual Meetings for Hepatic Sinusoidal Research Japan
• [Presentation] Novel Anti-Fibrotic Function of Neuroglobin in vitro and in vivo (2021)
  • Author(s): Vu Ngoc Hieu, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Ninh Quoc Dat, Katsutoshi Yoishizato and Norifumi Kawada
  • Organizer: Annual Meetings for Hepatic Sinusoidal Research Japan
• [Presentation] Anti-fibrosis application of overexpression and recombinant human CYGB in multiple models of advanced fibrosis (2021)
  • Author(s): Le Thi Thanh Thuy, Ninh Quoc Dat, Vu Ngoc Hieu, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada
  • Organizer: 29th Japan Gastroenterological Society Week
• [Presentation] Circulating soluble immune checkpoint proteins as biomarkers for predicting the outcome of antiviral treatment of chronic hepatitis B (2021)
  • Author(s): Hoang Hai, Masaru Enomoto, Minh Phuong Dong, Le Thi Thanh Thuy, Atsushi Hagihara, Sawako Uchida-Kobayashi, Akihiro Tamori, and Norifumi Kawada
  • Organizer: 29th Japan Gastroenterological Society Week
• [Presentation] Level of soluble immune checkpoint proteins associate with hepatocellular carcinoma development in patients with chronic hepatitis C (2021)
  • Author(s): Dong Minh Phuong, Le Thi Thanh Thuy, Hoang Hai, Akihiro Tamori, Masaru Enomoto, Sawako Uchida-Kobayashi and Norifumi Kawada
  • Organizer: The 57th Annual Meeting of the Japan Society of Hepatology
• [Presentation] Recombinant human Cytoglobin Deactivates Hepatic Stellate Cells and Prevents Fibrosis Aggravation by Scavenging ROS and Inducing Interferon-Beta (2021)
  • Author(s): Vu Ngoc Hieu, Ninh Quoc Dat, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada
  • Organizer: The 107th General Meeting of the Japanese Society of Gastroenterology
• [Presentation] Cytoglobin inhibits pancreatic cancer growth in vitro and in vivo (2021)
  • Author(s): 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
  • Organizer: The 107th General Meeting of the Japanese Society of Gastroenterology
• [Presentation] Hepatocellular carcinoma incidence with tenofovir vs entecavir in chronic hepatitis b: a systematic review and meta-analysis (2020)
  • Author(s): 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.
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] 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)
  • Author(s): Odagiri N, Enomoto M, Hai H, Le Thuy TT, Dong MP, Suoh M, Kotani K, Hagihara A, Uchida S, Tamori A, Kawada N.
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Recombinant human Cytoglobin scavenging ROS and inducing Interferon-Beta mediated hepatic stellate cells activation and liver fibrosis (2020)
  • Author(s): Vu Ngoc Hieu, Ninh Quoc Dat, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada
  • Organizer: 56th Annual Meeting of Japanese Society of Hepatology
• [Presentation] Recombinant human Cytoglobin Deactivates Hepatic Stellate Cells and Prevents Fibrosis Aggravation by Scavenging ROS and Inducing Interferon-Beta (2020)
  • Author(s): 1.Vu Ngoc Hieu, Ninh Quoc Dat, Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato and Norifumi Kawada.
  • Organizer: Symposium oral presentation at the 107th General Meeting of the Japanese Society of Gastroenterology
• [Presentation] Cytoglobin inhibits pancreatic cancer growth in vitro and in vivo (2020)
  • Author(s): 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
  • Organizer: 107th General Meeting of the Japanese Society of Gastroenterology
• [Presentation] 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)
  • Author(s): Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Vu Ngoc Hieu, Katsutoshi Yoishizato, and Norifumi Kawada.
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Cytoglobin protects mice from hepatic fibrosis and cancer induced by different aetiologies via scavenging reactive oxygen species (2019)
  • Author(s): Le Thi Thanh Thuy, Hoang Hai, Dinh Viet Hoang, Vu Ngoc Hieu, Ninh Quoc Dat, Katsutoshi Yoishizato, and Norifumi Kawada.
  • Organizer: Annual Meeting of American Association for the Study of Liver Diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Cytoglobin suppresses liver fibrosis and cancer in mice by regulating oxidative stress (2019)
  • Author(s): Le Thi Thanh Thuy, Ninh Quoc Dat, Hoang Hai, Dinh Viet Hoang, Katsutoshi Yoishizato, and Norifumi Kawada
  • Organizer: 55th Annual Meeting of Japanese Society of Hepatology
• [Presentation] The way to the science of a Vietnamese doctor (2019)
  • Author(s): Le Thi Thanh Thuy
  • Organizer: the 43rd Meeting of Western Branch of The Japan Society of Hepatology
  • Invited
• [Presentation] Chairman for the session of Biology and Medicine (2019)
  • Author(s): Le Thi Thanh Thuy
  • Organizer: Vietnam-Japan Science and Technology Symposium
  • Int'l Joint Research / Invited
• [Book] The Evolving Landscape of Liver Cirrhosis Management. Chapter 16: Antifibrotic therapy for liver cirrhosis. (2019)
  • Author(s): Le Thi Thanh Thuy, Hoang Hai, Vu Ngoc Hieu, Ninh Quoc Dat, Dinh Viet Hoang, and Norifumi Kawada.
  • Publisher: Springer Nature Singapore Pte Ltd
  • ISBN: 9789811379796
• [Patent(Industrial Property Rights)] 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)
  • Inventor(s): 河田 則文, LE THI THANH THUY
  • Industrial Property Rights Holder: 河田 則文, LE THI THANH THUY
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2021
• [Patent(Industrial Property Rights)] 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)
  • Inventor(s): 河田 則文, LE THI THANH THUY
  • Industrial Property Rights Holder: 河田 則文, LE THI THANH THUY
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019