Intestinal dysbiosis increases the risk of hepatocellular carcinoma - the study for protective mechanism against carcinoma using new animal models
| Project/Area Number |
18H02884
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 55020:Digestive surgery-related
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
柳川 徹 筑波大学, 医学医療系, 教授 (10312852)
有泉 俊一 東京女子医科大学, 医学部, 准教授 (40277158)
徳重 克年 東京女子医科大学, 医学部, 教授 (60188729)
蕨 栄治 筑波大学, 医学医療系, 講師 (70396612)
正田 純一 筑波大学, 医学医療系, 教授 (90241827)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | NASH / 肝癌 / 腸内細菌叢 / LPS / p62 / Nrf2 / ゲノム解析 / 遺伝子改変マウス / lipophagy / 遺伝子ノックインマウス / 脂肪性肝炎 / エンドトキシン / 腸管バリアー機能 / 遺伝子レスキューマウス / 腸管透過性 / 高カロリー食 / 遺伝子レスキュ－マウス / 非アルコール性脂肪性肝炎 / Kupffer細胞 / 肝星細胞 |
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| Outline of Final Research Achievements |
p62 and Nrf2 double knock-out mice exhibit the development of NASH and hepatocellular carcinoma (HCC) at the senile state. Influence of a high-fat diet (HFD) on the development of liver pathology was investigated. In the genomic analysis, HDF induced the decreased alpha-diversity of intestinal bacteria. The expression levels of LPS-binding protein were higher in the mice with HCC than in those without HCC. To explore the role of p62 in human NASH and HCC, tissue and cell-specific p62 gene rescue mice were generated. p62 in hepatocytes was considered to play a protective role against the development of NASH and HCC. Activation of p62 could be a promising target for the prevention and treatment of NASH and HCC.
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| Academic Significance and Societal Importance of the Research Achievements |
NASHは肝硬変，肝癌へ進行する慢性肝疾患である．しかし，その発症機序は未解明であり，NASH進行および肝癌発生を阻止するための薬物治療も確立していない．本研究は，DKOマウスに高脂肪食を摂餌させヒトNASHおよび肝癌に類似する新規モデルを作製したことにより，NASH-肝発癌のメカニズム解明に貢献すると考えられる．肝細胞のp62がNASHと肝癌に対して防御的な役割を果たすことを見出したことにより，p62が新しいNASHの治療標的と成り得る可能性を示した点で，将来的なNASH治療開発のための研究として意義が大きい．
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Report
(4 results)
Research Products
(42 results)
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[Journal Article] Gender difference in development of steatohepatitis in <i>p62/Sqstm1 and Nrf2</i> double-knockout mice2020
Author(s)
Watahiki T, Okada K, Warabi E, Nagaoka T, Suzuki H, Ishige K, Yanagawa T, Takahashi S, Mizokami Y, Tokushige K, Ariizumi SI, Yamamoto M, Shoda J
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Journal Title
Experimental Animals
Volume: 69
Issue: 4
Pages: 395-406
DOI
NAID
ISSN
0007-5124, 1341-1357, 1881-7122
Related Report
Peer Reviewed / Open Access
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[Journal Article] Surgical Outcomes of Hepatocellular Carcinoma With Bile Duct Tumor Thrombus: A Korea-Japan Multicenter Study.2019
Author(s)
Kim DS, Kim BW, Hasegawa K, Kudo A, Ariizumi S, Kubo S, Kim JM, Ahn KS, Choi SB, Jeong CY, Shima Y, Nagano H, Yamasaki O, Yamamoto M, et al.
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Journal Title
Related Report
Peer Reviewed
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[Journal Article] Characterization of HBV integration patterns and timing in liver cancer and HBV-infected livers.2018
Author(s)
Furuta M, Tanaka H, Shiraishi Y, Unida T, Imamura M, Fujimoto A, Fujita M, Sasaki-Oku A, Maejima K, Nakano K, Kawakami Y, Arihiro K, Aikata H, Ueno M, Hayami S, Ariizumi SI, Yamamoto M, et al.
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Journal Title
Oncotarget
Volume: 18
Pages: 25075-25088
Related Report
Peer Reviewed
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[Journal Article] Skeletal muscle mass to visceral fat area ratio is an important determinant affecting pathophysiology of NAFLD.2018
Author(s)
Shida T, Akiyama K, Oh S, Sawai A, Isobe T, Okamoto Y, Ishige K, Mizokami Y, Yamagata K, Onizawa K, Tanaka H, Iijima H, Shoda J
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Journal Title
J Gastroenterol
Volume: 53
Pages: 535-47
Related Report
Peer Reviewed
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