Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

Abstract

<p>Zearalenone (ZEA), a <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/secondary-metabolite" title="Learn more about secondary metabolite from ScienceDirect's AI-generated Topic Pages">secondary metabolite</a> of <em><a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/fusarium" title="Learn more about Fusarium from ScienceDirect's AI-generated Topic Pages">Fusarium</a></em> 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 <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transcriptomics" title="Learn more about transcriptomics from ScienceDirect's AI-generated Topic Pages">transcriptomics</a>, <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/metabolomics" title="Learn more about metabolomics from ScienceDirect's AI-generated Topic Pages">metabolomics</a>, <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/metagenomics" title="Learn more about metagenomics from ScienceDirect's AI-generated Topic Pages">metagenomics</a>, 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 <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/amino-acids" title="Learn more about amino acids from ScienceDirect's AI-generated Topic Pages">amino acids</a>, including <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/histidine" title="Learn more about histidine from ScienceDirect's AI-generated Topic Pages">histidine</a>, arginine, <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/citrulline" title="Learn more about citrulline from ScienceDirect's AI-generated Topic Pages">citrulline</a>, and glycine, decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/intestine-flora" title="Learn more about gut microbiota from ScienceDirect's AI-generated Topic Pages">gut microbiota</a> and reduced the abundance of nine genera, including <em>Tuzzerella</em> and <em>Rikenella</em>. Further association analysis indicated that <em>Tuzzerella</em> was negatively associated with the expression of BEST4 and DGKB genes, <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/uric-acid-blood-level" title="Learn more about serum uric acid from ScienceDirect's AI-generated Topic Pages">serum uric acid</a> levels, and tumor weight. Additionally, circulatory hippuric acid levels positively correlated with tumor weight and the expression of <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/oncogene" title="Learn more about oncogenic genes from ScienceDirect's AI-generated Topic Pages">oncogenic genes</a>, 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 <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/short-chain-fatty-acid" title="Learn more about short chain fatty acids from ScienceDirect's AI-generated Topic Pages">short chain fatty acids</a> production.<br></p>