| Summary: | 博士 === 臺灣大學 === 醫學檢驗暨生物技術學研究所 === 98 === Hepsin, a type II transmembrane serine protease, was indicated involve in hepatocyte growth, blastocyst hatching and blood coagulation pathway. Since there is no obvious abnormality in hepsin-deficient mice, the physiological functions of Hepsin are still unknown. It has also been reported that the overexpression of Hepsin in many cancer cell lines, especially in prostate cancer. Accordindingly, beside be concerned as a biomarker in cancer, many evidences show that Hepsin may play roles in tumor proliferation and metastasis, but the mechanism is not clear so far.
To evaluate the physiological functions of Hepsin, we challenged the tumor metastasis experiment in the hepsin knockout (KO) mice and found that the isogenic tumor cells colonized more efficiently to livers in the KO mice than that in the WT mice.To investigate this mechanism, we used intrasplenic injection and time course tracing strategies showed that both melanoma cells and the different sizes of fluorescent microbeads were more preferentially trapped in hepsin KO livers. With observation through transmission electron microscope and multiphoton intravital microscope, our results showed that the preferential retention of the tumor cells in the KO mice liver is due to the altered hepatic sinusoidal architecture tortured by the enlarged hepatocytes.
To delineate the mechanism responsible for the change of hepacyte sizes, we found the hepsin KO liver had increased Connexin proteins and the increased gap junctions are associated with changes of hepatocyte size. Further studies shown that hepatocyte growth factor (HGF) was associated with the expression level of Connexin proteins and the KO mice had decreased HGF in the liver microcirculation as well as in liver extracts. These observations demonstrate that hepsin involves in liver metastasis by regulating the diameter of the sinusoids and the volume of hepatocytes through its influence on HGF.
Our study provides evidence showing for the first time the relationships between hepsin and HGF/SF in vivo. We also provide a direct evidence of the relationship between successful tumor metastasis and the architecture of target organs. Our findings suggest the application of hepsin protein can be potential therapeutic approach to remission of the liver metastasis.
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