Studies on mechanism of inter cellular adhesion induced by cleavage of cancer cell surface HAI-1 protein and following enhancement of cancer metastasis.

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07047
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Yokohama City University
• Principal Investigator: Higashi Shouichi 横浜市立大学, 生命ナノシステム科学研究科(八景キャンパス), 教授 (10275076)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: HAI-1 / MMP-7 / マトリプターゼ / がん転移 / 細胞間接着 / コレステロール硫酸 / エンドサイトーシス / CRISPR-Cas9

Outline of Final Research Achievements

We previously found that matrix metalloproteinase-7 (MMP-7) induces homotypic adhesion of cancer cells by cleaving cell surface HAI-1 protein, a membrane-bound serine protease inhibitor. However, the detailed molecular mechanism remained to be clarified.
In the present study, we revealed that matriptase, one of the proteases susceptible for HAI-1 inhibition, contributes to the induction of the cancer cell aggregation. We also found that endocytosis of the cleaved HAI-1 led to enhance of membrane-bound matriptase activity and induction of the cell aggregation: dissociation of the cleaved inhibitor from active site of matriptase under mildly acidic conditions in the endosome probably causes exertion of the protease activity. It is likely that activities of MMP-7 and matriptase synergistically induce the cell aggregation via independent pathways. Further studies are needed to clarify these pathways.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

MMP-7を含むいくつかのMMPsはがん組織内で高発現しており、がんの増殖や転移を支えることから、MMPsの活性阻害剤は、従来の薬剤に代わるものとしてその開発が期待された。しかし、これまでに開発されたMMPs阻害剤は、個々のMMPに対する選択性が低く、副作用が原因となってがん治療薬としての利用に至っていない。
私たちが見出したMMP-7によるがん転移促進機構の全容解明は、そのユニークな機序を応用した副作用の少ない抗がん剤開発に繋がる可能性があり、学術的および社会的意義を持つと考える。