Sphingosine-1-phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy
Hironari Kawai
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Yosuke Osawa
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, Japan
Correspondence
Yosuke Osawa, Department of Gastroenterology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 239-2763, Japan.
Email: [email protected]
Tatsuya Kanto, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
Email: [email protected]
Search for more papers by this authorMichitaka Matsuda
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTomoyuki Tsunoda
Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Kanagawa, Japan
Search for more papers by this authorKeisuke Yanagida
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorDaisuke Hishikawa
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorMiku Okawara
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorYuzuru Sakamoto
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTomonari Shimagaki
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorYuriko Tsutsui
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorYuichi Yoshida
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorShiori Yoshikawa
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorKana Hashi
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorHiroyoshi Doi
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTaizo Mori
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTaiji Yamazoe
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorSachiyo Yoshio
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorMasaya Sugiyama
Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorDaisuke Okuzaki
Genome information Research Center, Research Institute for Microbial Disease, Osaka University, Suita, Osaka, Japan
Search for more papers by this authorHaruki Komatsu
Department of Pediatrics, Toho University Medical Center, Sakura hospital, Chiba, Japan
Search for more papers by this authorAyano Inui
Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Kanagawa, Japan
Search for more papers by this authorMiwa Tamura-Nakano
Communal Laboratory, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorChinatsu Oyama
Communal Laboratory, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorHideo Shindou
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
Department of Lipid Science, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorHironori Kusano
Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan
Search for more papers by this authorMasayoshi Kage
Kurume University Research Center for Innovative Cancer Therapy, Fukuoka, Japan
Search for more papers by this authorToru Ikegami
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Search for more papers by this authorKatsuhiko Yanaga
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Tatsuya Kanto
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Correspondence
Yosuke Osawa, Department of Gastroenterology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 239-2763, Japan.
Email: [email protected]
Tatsuya Kanto, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
Email: [email protected]
Search for more papers by this authorHironari Kawai
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Yosuke Osawa
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, Japan
Correspondence
Yosuke Osawa, Department of Gastroenterology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 239-2763, Japan.
Email: [email protected]
Tatsuya Kanto, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
Email: [email protected]
Search for more papers by this authorMichitaka Matsuda
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTomoyuki Tsunoda
Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Kanagawa, Japan
Search for more papers by this authorKeisuke Yanagida
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorDaisuke Hishikawa
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorMiku Okawara
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorYuzuru Sakamoto
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTomonari Shimagaki
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorYuriko Tsutsui
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorYuichi Yoshida
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorShiori Yoshikawa
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorKana Hashi
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorHiroyoshi Doi
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTaizo Mori
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorTaiji Yamazoe
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorSachiyo Yoshio
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorMasaya Sugiyama
Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan
Search for more papers by this authorDaisuke Okuzaki
Genome information Research Center, Research Institute for Microbial Disease, Osaka University, Suita, Osaka, Japan
Search for more papers by this authorHaruki Komatsu
Department of Pediatrics, Toho University Medical Center, Sakura hospital, Chiba, Japan
Search for more papers by this authorAyano Inui
Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Kanagawa, Japan
Search for more papers by this authorMiwa Tamura-Nakano
Communal Laboratory, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorChinatsu Oyama
Communal Laboratory, National Center for Global Health and Medicine, Tokyo, Japan
Search for more papers by this authorHideo Shindou
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan
Department of Lipid Science, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorHironori Kusano
Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan
Search for more papers by this authorMasayoshi Kage
Kurume University Research Center for Innovative Cancer Therapy, Fukuoka, Japan
Search for more papers by this authorToru Ikegami
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Search for more papers by this authorKatsuhiko Yanaga
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Tatsuya Kanto
The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan
Correspondence
Yosuke Osawa, Department of Gastroenterology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 239-2763, Japan.
Email: [email protected]
Tatsuya Kanto, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
Email: [email protected]
Search for more papers by this authorHironari Kawai and Yosuke Osawa contributed equally.
Funding information
This study was supported by grants from National Center for Global Health and Medicine to T.K. (29-shi-1007, 29-shi-2002, 30-shi-2001, 20A1002) and K. Yanagida (19A1023), Japan Agency for Medical Research and Development to H.S. (AMED-CREST 20gm0910011, AMED-P-CREATE 20cm0106116, AMED Program for Basic and Clinical Research on Hepatitis JP20fk0210041), Japan Society for the Promotion of Science KAKENHI to Y.O. (21K08014), International University of Health and Welfare Research Grant to Y.O., and The Jikei University Research Fund for Graduate Students to H. Kawai
Abstract
Background and Aims
Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and HCC. However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood.
Approach and Results
Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine-1-phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver.
Conclusions
In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.
CONFLICT OF INTEREST
The authors have declared that no conflict of interest exists.
Supporting Information
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| hep32256-sup-0001-FigS1.tifTIFF image, 4.1 MB | Fig S1 |
| hep32256-sup-0002-FigS2.tifTIFF image, 3.4 MB | Fig S2 |
| hep32256-sup-0003-FigS3.tifTIFF image, 4.6 MB | Fig S3 |
| hep32256-sup-0004-FigS4.tifTIFF image, 246.1 KB | Fig S4 |
| hep32256-sup-0005-FigS5.tifTIFF image, 1.6 MB | Fig S5 |
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| hep32256-sup-0007-FigS7.tifTIFF image, 3.7 MB | Fig S7 |
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| hep32256-sup-0009-FigS9.tifTIFF image, 418.9 KB | Fig S9 |
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| hep32256-sup-0011-FigS11.tifTIFF image, 424.4 KB | Fig S11 |
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| hep32256-sup-0017-FigS17.tifTIFF image, 1.7 MB | Fig S17 |
| hep32256-sup-0018-Supinfo.docxWord 2007 document , 87.6 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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