Development of anticancer therapy targeting ADAM9 and NK cells in HCC

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16723
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Showa University
• Principal Investigator: Jun Arai 昭和大学, 医学部, 講師 (30766176)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: MICA / NK細胞 / 肝細胞癌 / 癌免疫 / ロイコトリエン拮抗薬 / レチノイド / ADAM9 / レゴラフェニブ

Outline of Final Research Achievements

Background/Aim:The association between MICA and HCC development was identified in our previous genome-wide association study. Decreasing soluble MICA (sMICA) through MICA sheddases suppression facilitates natural killer (NK) cell-mediated cytotoxicity. The expression of ADAM9 in HCC has been correlated with poor prognosis, and our recent study showed that its suppression contributes to cancer elimination by decreasing sMICA. Materials and Methods: Human HCC cell line PLC/PRF/5 and HepG2 cells were used. sMICA levels were measured by ELISA. Expression of RXRs and RARs was knocked down by siRNA. Results: In our screening of FDA-approved drugs in vitro, two leukotriene receptor antagonists (LTRAs), and retinoids were found to be efficient ADAM9 inhibitors. Treatment with LTRAs and retinoids reduced MICA shedding in human HCC cells.
Conclusion: LTRAs and retinoids can be potential novel agents for HCC treatment.

Free Research Field

癌免疫

Academic Significance and Societal Importance of the Research Achievements

Natural killer細胞は腫瘍免疫の中心を担い、肝臓組織の約18％を占める。そのため正常な肝臓では癌細胞が発生しても、NK細胞により癌細胞が除去されやすい環境にある。我々はゲノムワイド関連解析によりC型肝炎の肝発癌に寄与する感受性遺伝子として抗NK細胞のリガンドであるMHC class I polypeptide-related sequence A（MICA）を同定した。今回新たにLTRAsとレチノイドがMICA切断抑止に寄与することを示した。
今後の肝臓病治療の目標として、肝癌予防法の発癌抑止法を検討すべき時代にさしかかっており、本課題は社会的にニーズの高い領域である。