| Research Abstract |
In this project, we have analyzed the roles of HGF-activating enzymes, their inhibitor HAI-1, and novel intestinal peptide H2RSP in the regenerative process of epithelial tissue, particularly of the digestive tracts.
HGF is activated in response to tissue injury. To date, HGF activator (HGFA), matriptase, hepsin have been reported to be responsible for this activation process. By using HGFA knockout (KO) mice, we have found that HGFA has important role in the process of epithelial restitution of injured intestinal mucosal tissue. Moreover, we also found that HGFA activity was important in the prevention of pulmonary fibrosis and in the process of B-cell maturation. Furthermore, we have identified KLK4 and KLK5 as novel and specific activating proteinases of pro-HGFA.
The activities of HGF-activating enzymes are regulated by a membrane-bound serine proteinase inhibitor, namely HAI-1 (HGFA inhibitor type 1). HAI-1 is abundantly expressed in the epithelial tissue such as gastrointestinal ep
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ithelium. We have developed HAI-1 KO mice. The KO mice were embryonic lethal due to impaired placental development. Then we intended to rescue the placental function in HAI-1 KO mice by chimera approach. After placental rescue, HAI-1-/- neonate was successfully delivered. However, they were lethal at 14 days after birth with significant skin phenotypes. Therefore HAI-1 has a critical role in the normal development and homeostasis of the skin. In order to further study the functions of HAI-1 in the gastrointestinal tracts, we decided to develop a conditional KO system for HAI-1 gene. Currently, the generation of floxed HAI-1 mice is underway.
The novel peptide, H2RSP, was abundantly expressed in the intestinal epithelium. H2RSP is a nuclear proteins and its nuclear translocation occurs in response to cellular differentiation. Interestingly, the nuclear localization of H2RSP was impaired in actively migrating epithelial cells during restitution. It was also downregulated in colon carcinoma cells. Rather surprisingly, invading cancer cells at the invasion front of colon cancer paradoxically expressed H2RSP and its subcellular localization was intracytoplasmic. Moreover, colon cancers with increased numbers of cytoplasmic H2RSP-positive cells at the invasion front showed enhanced lymph node metastases.
We also studied IGFBP2, an important regulator of IGF signaling, and found that IGFBP-2 is somehow involved in the invasion of glioblastoma cells. Then we have identified CD24 as an important downstream molecule of IGFBP-2-induced cellular invasiveness. Less
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