Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan.
Cancer Immunol Immunother. 2021 Jan;70(1):203-213. doi: 10.1007/s00262-020-02660-2. Epub 2020 Jul 18.
In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment.
在我们之前的全基因组关联研究中，我们证明了 MHC Ⅰ类相关链 A（MICA）与慢性丙型肝炎患者肝细胞癌（HCC）发展之间的关联。通过减少 MICA 脱落酶来增加癌细胞表面结合的 MICA（mMICA），有助于自然杀伤（NK）细胞介导的细胞毒性。我们最近的研究阐明了 A 型分解素和金属蛋白酶（ADAM），包括 ADAM9，是 HCC 中的 MICA 脱落酶，抑制 ADAMs 会增加 mMICA，证明了 mMICA-NK 靶向治疗的合理性。此外，我们表明regorafenib 可在转录和翻译水平上抑制 ADAM9。对 FDA 批准的药物库进行了筛选，以寻找更有效的 ADAM9 抑制剂。用各种候选药物处理后，通过流式细胞术评估 mMICA 的表达，发现白三烯受体拮抗剂是潜在的 ADAM9 抑制剂。此外，白三烯受体拮抗剂单独或与regorafenib 联合使用可上调 mMICA，而 mMICA 则通过 ADAM9 功能被白三烯 C4 和 D4 下调。我们的研究表明，白三烯受体拮抗剂可作为新型免疫控制药物和 HCC 中 ADAM9 的抑制剂开发。此外，应探索白三烯受体拮抗剂作为与传统多激酶抑制剂联合治疗的伙伴，以开发用于 HCC 管理和治疗的增效治疗策略。
