Recent evidence indicates that a high-fat diet (HFD) can promote tumor development, especially colorectal cancer (CRC), by influencing the microbiota. Regulatory circular RNAs (circRNAs) play an important role in modulating host–microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a HFD modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein referred to as circ_0126925) in CRC. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumours from limited branched-chain amino acids (BCAAs) interference by improving the metabolism of BCAAs in CRC. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of CRC by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host–microbe interactions in CRC.
Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome related pathology in humans.
Background:5-fluorouracil (5-FU) is a widely used drug for cancer treatment, but its effect and underlying mechanisms on osteosarcoma (OS) cells remain unclear.Methods:U2OS and MG63 cells were treated with 0, 50, 100, and 500 μM 5-FU. MTS and flow cytometry were used to examine the effect of 5-FU on cell viability and apoptosis, respectively. Circular RNA (circRNA) expression was detected using RNA sequencing and quantitative real-time PCR (qPCR). Differentially expressed circRNAs were further subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis to predict their functions. A circRNA–miRNA–mRNA interaction network was generated to analyze the regulatory networks of 5-FU–induced differentially expressed circRNAs. Western blotting (WB) was used to verify the protein in the downstream of circRNAs.Results:5-FU inhibited the cell viability of the MG63 cells in a concentration-dependent manner. The most significant effect was observed in the cells treated with 500 μM 5-FU. Apoptosis was also increased in the MG63 cells after 500 μM 5-FU treatment for 3 days. RNA sequencing results showed that 183 differentially expressed circRNAs (172 upregulated and 11 downregulated) in 5-FU–treated cells. KEGG and GO analysis showed that the differentially expressed circRNAs were primarily enriched in proliferation-, apoptosis-, and metabolism-related functions. qPCR was used to verify the most upregulated and downregulated circRNAs. The circRNA–miRNA–mRNA interaction network showed that these 8 circRNAs had a sizable regulatory network that links a series of genes involved in tumor suppression.Conclusion:5-FU treatment resulted in the differentially expressed circRNAs that were proliferation- and apoptosis-associated and were involved in the 5-FU–induced inhibition of tumor proliferation in OS cells.
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