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Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells by hepatocyte growth factor signaling in mice
Author(s) -
Hsu YuChen,
Huang HsiangPo,
Yu IShing,
Su KangYi,
Lin ShuRung,
Lin WeiChou,
Wu HuaLin,
Shi GueyYueh,
Tao MiHua,
Kao ChengHeng,
Wu YaoMing,
Martin Patricia E.,
Lin ShihYao,
Yang PanChyr,
Lin ShuWha
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25773
Subject(s) - hepatocyte growth factor , biology , cancer research , tumor progression , proteases , microbiology and biotechnology , cancer , receptor , biochemistry , genetics , enzyme
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. (H EPATOLOGY 2012;56:1913–1923)