Abstract
Colorectal cancer has high morbidity and mortality worldwide, especially in western countries; the incidence of colorectal cancer has been high, which is closely related to the high intake of red meat; and the N-glycolylneuraminic acid (Neu5Gc) is responsible for red meat-induced colorectal cancer. A large number of previous studies have suggested that exogenous Neu5Gc-activated inflammation induced the occurrence of colorectal cancer. However, it has not been known whether the Neu5Gc has a direct inducing effect on colorectal cancer. In this study, we found that Neu5Gc promoted the proliferation of colorectal cancer cells and normal intestinal epithelial cells, and further screened out 98 Neu5Gc targets related to the occurrence and development of colorectal cancer by network pharmacology. Subsequently, GO and KEGG enrichment analyses of these targets revealed that mainly enriched in the PI3K-Akt signaling pathway. Then, we selected SRC, HRAS, CDK2, CCNA2, and AKT2 as core targets based on the phenomena of the previous experiments and the available literature reports, and then we used AutoDock for molecular docking with Neu5Gc; the results found that these five genes could bind to Neu5Gc stably. In vitro experiments showed that the mRNA levels of SRC, HRAS, AKT2, CDK2, and CCNA2 were upregulated and the protein levels of HRAS, AKT2, and CCNA2 were enhanced in FHC and SW620 cells after Neu5Gc (100 ng/mL) treatment. In conclusion, this study revealed that Neu5Gc probably acted as a carcinogen that stimulates the expression of proto-oncogene HRAS and the PI3K-Akt pathway and accelerated cell cycle progression. These findings revealed a novel mechanism that Neu5Gc promoted the occurrence and development of colorectal cancer.
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Abbreviations
- Neu5Gc:
-
N-glycolylneuraminic acid
- CRC:
-
Colorectal cancer
- MTT:
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- CMAH:
-
Cytidine monophosphate-N-acetylneuraminic acid hydroxylase
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- GO:
-
Gene Ontology
- FBS:
-
Fetal bovine serum
- BP:
-
Biological processes
- CC:
-
Cellular components
- MF:
-
Molecular functions
- ANOVA:
-
One-way analysis of variance
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Funding
This study was supported by the National Natural Science Foundation of China (No. 32072220), Shanxi Province Science Foundation for Youths (201901D211128), Shanxi Province Science Foundation for Key Project (International Science and Technology Cooperation, 201903D421055), Project of the Central Government Guiding Local Science and Technology (No. YDZJSX2022A006), and Shanxi Postgraduate Education Innovation Project (2022Y112).
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Ya-Ning Liu and Jing-Yi Liang assisted with cell experiment. Shu-Ning Yan and Yu Chen assisted with network analysis. Li-Chao Zhang, Xiao-Qin La, and Zhuo-Yu Li designed the experiments. Li-Chao Zhang and Ya-Ning Liu wrote and revised the manuscript. All authors read and approved the manuscript and all data were generated in-house and that no paper mill was used.
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Zhang, LC., Liu, YN., La, XQ. et al. The potential mechanism of Neu5Gc inducing colorectal cancer based on network pharmacology and experimental validation. Naunyn-Schmiedeberg's Arch Pharmacol 396, 705–718 (2023). https://doi.org/10.1007/s00210-022-02345-w
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DOI: https://doi.org/10.1007/s00210-022-02345-w