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 Apc^Min/+ 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.

中文翻译：

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白藜芦醇通过抑制 LEF1 抑制结直肠腺瘤的发展；使用连接图进行综合分析

尽管已经报道了许多关于结直肠肿瘤的化学预防研究，但目前尚无有效且安全的预防剂。我们通过使用连接图 (CMAP) 分析结合结直肠腺瘤 (CRA) 患者来源的类器官 (PDO) 的体外筛选，从美国食品和药物管理局 (FDA) 批准的化合物中全面搜索了针对结直肠肿瘤的候选预防化合物。我们根据 CRA 和正常上皮标本的 DNA 微阵列分析生成了 CRA 特异性基因特征，将它们应用于 1309 种 FDA 批准的化合物的 CMAP 分析，并确定了 121 种应该取消基因特征的候选化合物。我们将它们缩小到 15 种化合物，并评估了它们对体外 CRA-PDO 生长的抑制作用。我们终于确定了白藜芦醇，多酚类植物化学物质之一，作为一种化合物，与正常上皮 PDO 相比，对 CRA-PDO 的生长显示出最强的抑制作用。当向 Apc 施用白藜芦醇时^Min/+小鼠在 15 或 30 mg/kg 时，与对照小鼠相比，两组的息肉（腺瘤）数量均显着减少。同样，与对照大鼠相比，用 10 或 100 毫克/白藜芦醇处理的偶氮甲烷注射大鼠的息肉（腺瘤）数量显着减少。对经白藜芦醇处理的大鼠的腺瘤进行的微阵列分析揭示了 LEF1 表达的最大变化（下调），LEF1 是 Wnt 信号通路中的关键分子。用白藜芦醇处理可显着下调 CRA-PDO 中的 Wnt 靶基因 (MYC)。我们的数据表明，白藜芦醇可能是化学预防结直肠肿瘤最有效的化合物，其功效是通过抑制 Wnt 信号通路中的 LEF1 表达来介导的。