Post-translational Modifications of RNA-binding Proteins in obesity-associated colorectal carcinogenesis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08350
• 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: Yamagata University
• Principal Investigator: Sasaki Yu 山形大学, 医学部, 講師 (60466620)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 大腸癌 / 大腸腺腫 / 肥満 / 代謝 / メタボリックシンドローム / インスリン抵抗性 / RNA修飾

Outline of Final Research Achievements

The expression of HuR in the cytoplasm exhibited an increase in colorectal cancers among individuals with obesity. Additionally, in colon cancer cell lines, insulin induced the translocation of HuR from the nucleus to the cytoplasm and significantly augmented the mRNA binding to HuR by at least a fourfold increase. Through a comprehensive transcriptome analysis, I identified 38 mRNAs with a more than twofold enhanced binding affinity to HuR. Notably, the X gene, which displayed the most substantial decrease in binding, experienced a 50% reduction in mRNA stability. Intriguingly, knockout mice lacking this gene exhibited lymphoma-like tumor growth in the small intestine. Further investigation will elucidate the precise mechanism by which HuR-mediated post-transcriptional regulation of RNA contributes to colon carcinogenesis. Moreover, these findings will lay the foundation for developing novel molecular strategies to effectively prevent and treat colon cancer.

Free Research Field

消化器病学

Academic Significance and Societal Importance of the Research Achievements

本研究では、肥満関連大腸癌におけるRNA結合蛋白HuRの核細胞質移行や標的mRNAsの変化、および大腸癌の発育進展に関わる可能性のある新規の標的遺伝子を明らかにしました。代謝変化によるHuRを介したRNA転写後制御の変調が肥満関連大腸発癌を導くという新しい機序を解明し、それを制御する方策を見出すことで、世界的に増えている肥満関連大腸癌の征圧につなげることが期待できます。