Investigation of potential therapeutic strategies for esophageal squamous cell carcinoma focused on the functional modification of cancer stimulating RNA editing.

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07910
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: MASUDA Kiyoshi 川崎医科大学, 医学部, 教授 (00457318)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: RNA編集 / RNA結合蛋白質 / 食道癌

Outline of Final Research Achievements

We found that ADAR1 was highly expressed in esophageal squamous cell carcinoma (ESCC). Knockdown of ADAR1 suppressed cell proliferation. Comprehensive analysis using microarrays suggested that ADAR1 may suppress the immune response and apoptosis and contribute to the survival of cancer cells. In ADAR1 knockdown cells, the binding between the target genes and cancer stimulating RBPs (csRBPs) were increased/decreased and then the amounts of mRNAs were altered. These results suggested that ADAR1 may cause A-to-I RNA editing in the 3’UTR of mRNAs that control cell growth, infiltration, and cancer immunity, and regulate association between csRBP and target mRNAs. In conclusion, ADAR1 may be a hub factor that induces disruption of the post-transcriptional regulatory mechanism in ESCC cells.

Free Research Field

RNA生物学

Academic Significance and Societal Importance of the Research Achievements

これまで、RNA編集異常の病態への関与は、神経変性疾患や精神疾患、一部の希少疾患で報告されているが、これらの分子機構は不明である。癌組織は正常組織に比べRNA編集活性が亢進しており、癌特異的なRNA編集パターンが見られることから、RNA編集不全と発癌との関連性が示唆されているが、癌特異的なRNA編集のほとんどが非翻訳領域に集中しており、機能予測が困難なことから、これらを直接結びつける分子機構の解明には至っていない。本研究結果は、食道癌におけるRBPが作る大きな機能モジュール内でのRNA編集の生物学的意義解明の端緒となる。