Zearalenone (ZEA), a secondary metabolite of Fusarium fungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancer cells in vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer-promoting effects of ZEA. This study aimed to determine the effect of ZEA on colon cancer progression and its underlying mechanisms. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed a twofold increase in tumor weight with the 4-week ZEA intervention. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB, and Ki67 and the phosphorylation levels of ERK1/2 and AKT. Serum metabolomic analysis revealed that the levels of amino acids, including histidine, arginine, citrulline, and glycine, decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of nine genera, including Tuzzerella and Rikenella. Further association analysis indicated that Tuzzerella was negatively associated with the expression of BEST4 and DGKB genes, serum uric acid levels, and tumor weight. Additionally, circulatory hippuric acid levels positively correlated with tumor weight and the expression of oncogenic genes, including ROBO3, JAK3, and BEST4. Altogether, our results indicated that ZEA promotes colon cancer progression by enhancing the BEST4/AKT/ERK1/2 pathway, lowering circulatory amino acid concentrations, altering gut microbiota composition, and suppressing short chain fatty acids production.

中文翻译：

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使用综合多组学方法对小鼠玉米赤霉烯酮加速结直肠癌的机制洞察

玉米赤霉烯酮 (ZEA) 是一种在谷类食品中发现的镰刀菌的次级代谢产物，可在体外促进结肠、乳腺癌和前列腺癌细胞的生长。然而，缺乏动物研究阻碍了对 ZEA 促癌作用的更深入的机制理解。本研究旨在确定 ZEA 对结肠癌进展的影响及其潜在机制。通过转录组学、代谢组学、宏基因组学和宿主表型的综合分析，我们调查了 4 周 ZEA 干预对异种移植小鼠结直肠癌的影响。我们的结果显示，经过 4 周的 ZEA 干预后，肿瘤重量增加了两倍。ZEA 暴露显着增加了 BEST4、DGKB 和 Ki67 的 mRNA 和蛋白质水平以及 ERK1/2 和 AKT 的磷酸化水平。血清代谢组学分析显示，ZEA 组的氨基酸水平（包括组氨酸、精氨酸、瓜氨酸和甘氨酸）显着降低。此外，ZEA 降低了肠道微生物群的 alpha 多样性并减少了九个属的丰度，包括 Tuzzerella 和 Rikenella。进一步的关联分析表明，Tuzzerella 与 BEST4 和 DGKB 基因的表达、血清尿酸水平和肿瘤重量呈负相关。此外，循环马尿酸水平与肿瘤重量和致癌基因（包括 ROBO3、JAK3 和 BEST4）的表达呈正相关。总而言之，我们的结果表明 ZEA 通过增强 BEST4/AKT/ERK1/2 通路、降低循环氨基酸浓度、改变肠道微生物群组成、