Elucidation of the relationship between cancer malignancy and RNA modification

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07688
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo University of Science (2021); Osaka University (2019-2020)
• Principal Investigator: Konno Masamitsu 東京理科大学, 研究推進機構生命医科学研究所, 助教 (80618207)
• Co-Investigator(Kenkyū-buntansha): 石井 秀始 大阪大学, 医学系研究科, 特任教授(常勤) (10280736) ; 小関 準 名古屋大学, 医学系研究科, 准教授 (20616669)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 膵臓がん / エピトランスクリプトーム

Outline of Final Research Achievements

pancreatic cancer's 5-year survival rate is about 7% and the time to survive from the time of diagnosis is 14 months. So pancreatic cancer is a very serious. Therefore, the development of novel anticancer agents based on the mechanism of pancreatic cancer malignant transformation is an urgent and pressing issue to improve treatment outcomes. In our previous studies, we have shown that the expression of METTL3, an RNA methyltransferase, leads to the malignant transformation of pancreatic cancer. So in this study, we aimed to develop inhibitors of the RNA methyltransferase METTL3. We tried to screening for METTL3 inhibitors and evaluated their antitumor activity in mice. As a result, we succeeded in obtaining several lead compounds that inhibit METTL3.

Free Research Field

エピトランスクリプトーム

Academic Significance and Societal Importance of the Research Achievements

METTL3の発言が高い膵臓がんマウスの腫瘍は増殖が非常に速く、転移も引き起こし、生存率が非常に悪いことが明らかとなった。さらに詳細なメカニズム解析を行ったところ、METTL3は特に免疫関連遺伝子のmRNAのメチル化を亢進しており、その結果PD1, PDL1を含む免疫関連タンパク質の発現量を増加させ、自己免疫からの攻撃を回避するシステムを獲得していることが明らかとなった。つまり本研究で獲得したMETTL3の阻害剤はPL1、PDL1、CTLA4 抗体に続く新たながん免疫製剤となる可能性を秘めている。