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Liver Biology/Pathobiology

Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice†‡

  1. Yu-Chen Hsu1,7,
  2. Hsiang-Po Huang2,
  3. I-Shing Yu1,
  4. Kang-Yi Su7,8,
  5. Shu-Rung Lin9,
  6. Wei-Chou Lin3,
  7. Hua-Lin Wu10,11,
  8. Guey-Yueh Shi10,11,
  9. Mi-Hua Tao12,
  10. Cheng-Heng Kao13,
  11. Yao-Ming Wu4,
  12. Patricia E. Martin14,
  13. Shih-Yao Lin15,
  14. Pan-Chyr Yang5,7,12,
  15. Shu-Wha Lin1,6,7,§,*

Article first published online: 9 OCT 2012

DOI: 10.1002/hep.25773

Issue

Hepatology

Hepatology

Volume 56, Issue 5, pages 1913–1923, November 2012

Additional Information

How to Cite

Hsu, Y.-C., Huang, H.-P., Yu, I.-S., Su, K.-Y., Lin, S.-R., Lin, W.-C., Wu, H.-L., Shi, G.-Y., Tao, M.-H., Kao, C.-H., Wu, Y.-M., Martin, P. E., Lin, S.-Y., Yang, P.-C. and Lin, S.-W. (2012), Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice. Hepatology, 56: 1913–1923. doi: 10.1002/hep.25773

Author Information

  1. 1

    Department of Clinical Laboratory Sciences and Medical Biotechnology,National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

  2. 2

    Department of Medical Research and Department of Pediatrics,National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

  3. 3

    Department of Pathology,National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

  4. 4

    Department of Surgery,National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

  5. 5

    Department of Internal Medicine,National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

  6. 6

    Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

  7. 7

    Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan

  8. 8

    Institute of Statistical Science, Chung-Yuan Christian University, Taoyuan, Taiwan

  9. 9

    Department of Bioscience Technology, College of Science, Chung-Yuan Christian University, Taoyuan, Taiwan

  10. 10

    Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

  11. 11

    Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

  12. 12

    Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

  13. 13

    Center for General Education, Chang Gung University, Taoyuan, Taiwan

  14. 14

    Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK

  15. 15

    AbGenomics International Inc., Taipei, Taiwan

  1. §

    Fax: 886-2-2381-7083

*Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, No.7 Chung-Shan S. Road, Taipei 10002, Taiwan

  1. †

    Potential conflict of interest: Nothing to report.

  2. ‡

    This work was supported by grants (to S.W.L.) from the National Science Council (grant nos.: NSC93-2314-B002-276, NSC94-2320-B002-092, 95-2320-B-002-054, NSC95-3112-B-002-017, 96-3112-B-002-023, and NSC98-3112-B-002-030), the National Health Research Institutes (grant nos.: NHRI-EX90-9142SI, NHRI-EX91-9142SI, NHRI-EX92-9192SI, and NHRI-EX99-9729BI), National Taiwan University Hospital, Taiwan (grant nos.: 90A01 and 91A06), and a grant (to H.P.H.) from the National Science Council (NSC 97-2321-B-002-020-MY3).

  3. §

    Fax: 886-2-2381-7083

Publication History

  1. Issue published online: 31 OCT 2012
  2. Article first published online: 9 OCT 2012
  3. Accepted manuscript online: 13 APR 2012 12:44PM EST
  4. Manuscript Accepted: 30 MAR 2012
  5. Manuscript Received: 31 OCT 2011

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Abstract

The liver architecture plays an important role in maintaining hemodynamic balance, but the mechanisms that underlie this role are not fully understood. Hepsin, a type II transmembrane serine protease, is predominantly expressed in the liver, but has no known physiological functions. Here, we report that hemodynamic balance in the liver is regulated through hepsin. Deletion of hepsin (hepsin−/−) in mice resulted in enlarged hepatocytes and narrowed liver sinusoids. Using fluorescent microbeads and antihepsin treatment, we demonstrated that metastatic cancer cells preferentially colonized the hepsin−/− mouse liver as a result of the retention of tumor cells because of narrower sinusoids. The enlarged hepatocytes expressed increased levels of connexin, which resulted from defective prohepatocyte growth factor (pro-HGF) processing and decreased c-Met phosphorylation in the livers of hepsin−/− mice. Treatment of hepsin−/− mice with recombinant HGF rescued these phenotypes, and treatment of wild-type mice with an HGF antagonist recapitulated the phenotypes observed in hepsin−/− mice. Conclusion: Our findings show that the maintenance of hepatic structural homeostasis occurs through HGF/c-Met/connexin signaling by hepsin, and hepsin-mediated changes in liver architecture significantly enhance tumor metastasis to the liver. (HEPATOLOGY 2012;56:1913–1923)

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