Post-translational Modifications of RNA-binding Proteins in obesity-associated colorectal carcinogenesis
| Project/Area Number |
20K08350
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Yamagata University |
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Principal Investigator |
Sasaki Yu 山形大学, 医学部, 講師 (60466620)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| 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 / HuR / RNA転写後調節 / RNAシークエンス / 大腸がん / GIP / インクレチン / 大腸発がん |
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| Outline of Research at the Start |
本邦をはじめ世界的な大腸癌増加の主な要因として肥満、メタボリックシンドロームの増加がある。この病態の中核にはインスリン抵抗性やアディポサイトカイン分泌異常、慢性低炎症状態があるが、このような変調がどのように大腸癌を引き起こすのか、その分子機序は不明な点が多い。
本研究ではRNA結合蛋白HuRに着目し、肥満関連大腸がんにおいて、代謝異常と関連したHuRの細胞内局在の変化、標的mRNAの同定とその安定性について明らかにする。これにより、肥満、代謝異常からの大腸発がんにおける、HuRによるRNAの転写後調節を介した発がん機序を明らかにし、それに基づいた予防や治療を可能とする新しい分子基盤を創出する。
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| 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.
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| 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。
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Report
(4 results)
Research Products
(20 results)
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[Journal Article] Insulin and glucose altered AMPK-TET2-5hmC axix toward on the obesity-related colorectal cancer development2021
Author(s)
Takashi Kon, Yu Sasaki, Yasuhiko Abe, Yusuke Onozato, Makoto Yagi, Naoko Mizumoto, Takayuki Sakai, Matsuki Umehara, Minami Ito, Ayumi Koseki, Yoshiyuki Ueno
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Journal Title
Gastroenterology
Volume: 160
Related Report
Peer Reviewed
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[Presentation] Ectopic fat accumulation in the liver and pancreas in patients with colorectal adenoma2020
Author(s)
Yu Sasaki, Yasuhiko Abe, Shoichi Nishise, Takao Yaoita, Makoto Yagi, Naoko Mizumoto, Masakuni Shoji, Yusuke Onozato, Takashi Kon, Takayuki Sakai, Yoshiyuki Ueno
Organizer
American Gastroenterological Association, DDW2020
Related Report
Int'l Joint Research
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[Presentation] Changes in the gut microbiota and their effect on pathogenesis in obese patients with colorectal cancer2020
Author(s)
Masakuni Shoji, Yu Sasaki, Yasuhiko Abe, Shoichi Nishise, Takao Yaoita, Makoto Yagi, Naoko Mizumoto, Yusuke Onozato, Takashi Kon, Takayuki Sakai, Ayumi Koseki, Hidenori Sato, Yoshiyuki Ueno
Organizer
American Gastroenterological Association, DDW2020
Related Report
Int'l Joint Research
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[Presentation] Obesity and colorectal neoplasm: identifying obesity-associated somatic genomic signals from colorectal adenoma and carcinoma2020
Author(s)
Takashi Kon, Yu Sasaki, Yasuhiko Abe, Takao Yaoita, Makoto Yagi, Naoko Mizumoto, Masakuni Shoji, Yusuke Onozato, Takayuki Sakai, Ayumi Koseki, Hidenori Sato, Yoshiyuki Ueno
Organizer
American Gastroenterological Association, DDW2020
Related Report
Int'l Joint Research
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