Development of a novel esophageal cancer treatment focusing on controlling cancer-promoting branch points

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07971
• 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): 2021-04-01 – 2024-03-31
• Keywords: RNA結合蛋白質 / 食道扁平上皮癌 / 転写後調節機構

Outline of Final Research Achievements

We focused on the alternative splicing control mechanism of the TIA1 gene and the phosphorylation regulators of TIA1a during the pathogenesis of esophageal squamous cell carcinoma (ESCC). We predicted multiple phosphorylation kinases based on the amino acid sequence of TIA1a and identified a kinase (kinase2: lab name) that controls the intracellular localization of TIA1a. In addition, a splicing factor (SF-X: lab name) that could induce TIA1a-type splicing was identified by knockdown experiments. Specific siRNAs and inhibitors against these identified factors significantly suppressed the cell growth of ESCC cells. RNA-seq data analysis confirmed that TIA1a, kinase2, and SF-X expression levels increased dramatically in ESCC tissues compared to normal tissues. Moreover, there was a positive correlation between TIA1a levels, kinase2 levels, and SF-X levels. These results suggest that the identified factors could be novel therapeutic targets for ESCC.

Free Research Field

RNA生物学

Academic Significance and Societal Importance of the Research Achievements

RBPは正常細胞でも様々な生理機能を担っており、発現量制御に着目した従来の治療戦略では重大な副作用が予測される。本研究の成果をモデルに、RBPが癌細胞の悪性形質獲得のために必要な機能モジュール群のみを調節する分子機構の全貌を解明し、これを可逆的にON/OFFすることでこの機能モジュール全体を特異的に調節できれば、有効な分子標的治療薬の少ないESCCにおいて、腫瘍や特定の悪性形質に選択性が高い治療法開発が可能になる。