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ID 117988
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ResveratrolはLEF1を抑制することで大腸腺腫の発生を抑制する;connectivity mapを用いた網羅的解析
著者
和田, 浩典 徳島大学大学院医学研究科(医学専攻)
Fujimoto, Shota Tokushima University
板東, 正浩 Tokushima University
Horimoto, Katsuhisa National Institute of Advanced Industrial Science and Technology|SOCIUM
Matsuzawa, Yui National Cancer Center
Mutoh, Michihiro National Cancer Center|Kyoto Prefectural University of Medicine
キーワード
chemoprevention
colorectal adenoma
connectivity map
LEF1
resveratrol
資料タイプ
学位論文
抄録
Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to ApcMin/+ mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway.
掲載誌名
Cancer Science
ISSN
13497006
出版者
Japanese Cancer Association|John Wiley & Sons
113
12
開始ページ
4374
終了ページ
4384
発行日
2022-09-09
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Hironori Wadaの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3670号
学位記番号
甲医第1552号
学位授与年月日
2023-01-26
学位名
博士(医学)
学位授与機関
徳島大学
部局
医学系
病院