TY - JOUR
T1 - Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches
AU - Lo, Emily Kwun Kwan
AU - Wang, Xiuwan
AU - Lee, Pui Kei
AU - Lee, Jetty Chung Yung
AU - Gómez-Gallego, Carlos
AU - Zhao, Danyue
AU - El-Nezami, Hani
AU - Li, Jun
AU - Wong , Ho Ching
N1 - Funding Information:
The authors thank Mr. Oscar Chow for providing technical assistance. The authors are grateful to Dr. Sam Leung Kin Sum for providing the preliminary data on SCFAs. Fig. 1A was created with BioRender.com. This study was supported by the Shenzhen Basic Research Program (JCYJ20190808182402941), Guangdong Basic and Applied Research Major Program (2019B030302005), Collaborative Research Fund (C7013-19GF) in Hong Kong, City University of Hong Kong Internal Grant (7005756, 9678247, 9680310), and PolyU Start-up Fund (1-BE3H). Supplementary data for this article can be found at https://doi.org/xxxx. Fig. S1: Effect of Zearalenone in body weight, feed consumption and vital organ weight of xenograft mice; Fig. S2: Heatmap of log-transformed expression levels (in the form of FPKM values) of all differentially expressed genes identified by DESeq2 at padj < 0.1; Fig. S3: Correlations between ZEA treatment and potential oncogenic signaling; Fig. S4: Effect of ZEA treatment on metabolites in serum samples; Fig. S5: Heatmap of log-transformed relative abundance of significantly (FDR < 0.05) different genera between control and ZEA detected by ANCOM-BC; Fig. S6: Effect on the SCFA levels in the cecal contents upon treatment; Fig. S7: qPCR analysis of the mRNA expression of BEST4; Fig. S8: Transcriptional changes in tumor cells in response to ZEA treatment; Table S1: Amino acids that were altered by ZEA treatment compared to control group; Table S2: List of metabolites detected in serum samples of control and experimental groups using Progenesis QI; Table S3: Metabolites strongly related to tumor weight with spearman's rank correlation coefficient; Table S4: Pearson correlation coefficient and significance level for DA metabolites, DE genes and DA genera; Supplementary methods: RNA extraction and Real time reverse transcription polymerase chain reaction (RT-qPCR).
Funding Information:
The authors thank Mr. Oscar Chow for providing technical assistance. The authors are grateful to Dr. Sam Leung Kin Sum for providing the preliminary data on SCFAs. Fig. 1 A was created with BioRender.com. This study was supported by the Shenzhen Basic Research Program ( JCYJ20190808182402941 ), Guangdong Basic and Applied Research Major Program ( 2019B030302005 ), Collaborative Research Fund ( C7013-19GF ) in Hong Kong, City University of Hong Kong Internal Grant ( 7005756 , 9678247 , 9680310 ), and PolyU Start-up Fund ( 1-BE3H ).
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
KW - Colon cancer
KW - Gut microbiota
KW - Metabolomics
KW - Multi-omics
KW - RNA-Seq
KW - Zearalenone
UR - https://www.scopus.com/pages/publications/85149441971
U2 - 10.1016/j.csbj.2023.02.048
DO - 10.1016/j.csbj.2023.02.048
M3 - Journal article
AN - SCOPUS:85149441971
SN - 2001-0370
VL - 21
SP - 1785
EP - 1796
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
ER -
