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other·preclinical research, oncology, biomedical research, gastroenterology·PMC10006464

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

Computational and Structural Biotechnology Journal · 9 authors, 7 centres

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TL;DR

This preclinical study used a colon cancer xenograft mouse model to investigate how the mycotoxin zearalenone (ZEA) promotes tumor growth. It found that ZEA exposure accelerated tumor development by altering the gut microbiota, serum metabolites, and activating specific cancer-related pathways.

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Key results showed that ZEA exposure promoted tumor growth, which was associated with the upregulation of the BEST4/AKT/ERK1/2 signaling pathway, reduced serum amino acid levels, and altered gut microbiota composition, including decreased short-chain fatty acid-producing bacteria. The findings provide mechanistic insights into a potential environmental risk factor for CRC but require further validation in humanized models or human studies.

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other

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preclinical research

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ORIGINAL PAPER

PMC10006464

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

Computational and Structural Biotechnology Journal

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ABSTRACT

Abstract 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. Keywords: Zearalenone, Colon cancer, RNA-Seq, Gut microbiota, Metabolomics, Multi-omics

CITATION EXPORT

Emily Kwun Kwan Lo, Xiuwan Wang, Pui-Kei Lee et al.. Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches. Computational and Structural Biotechnology Journal. (2023). https://doi.org/10.1016/j.csbj.2023.02.048

AUTHORS

9 · 7 CENTRES

Emily Kwun Kwan Lo, Xiuwan Wang, Pui-Kei Lee, Ho-Ching Wong, Jetty Chung-Yung Lee, Carlos Gómez-Gallego, Danyue Zhao, Hani El-Nezami, Jun Li

aSchool of Biological Sciences, University of Hong Kong, Pokfulam 999077, Hong Kong, China
bDepartment of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
cDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
dInstitute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland
eResearch Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China
fDepartment of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong, China
gSchool of Data Science, City University of Hong Kong, Hong Kong, China