Gut microbiota regulate tumor metastasis via circRNA/miRNA networks

Abstract

Background: Increasing evidence indicates that gut microbiota plays an important role in cancer progression. However, the underlying mechanism remains largely unknown. Here, we report that broad-spectrum antibiotics (ABX) treatment leads to enhanced metastasis by the alteration of gut microbiome composition. Methods: Cancer LLC and B16-F10 cell metastasis mouse models, and microarray/RNA sequencing analysis were used to reveal the regulatory functions of microbiota-mediated circular RNA (circRNA)/microRNA (miRNA) networks that may contribute to cancer metastasis. Results: The specific pathogen-free (SPF) mice with ABX treatment demonstrated enhanced lung metastasis. Fecal microbiota transplantation (FMT) from SPF mice or Bifidobacterium into germ-free mice significantly suppressed lung metastasis. Mechanistically, gut microbiota impacts circRNA expression to regulate levels of corresponding miRNAs. Specifically, such modulations of gut microbiota inhibit mmu_circ_0000730 expression in an IL-11-dependent manner. Bioinformatics analysis combined with luciferase reporter assays revealed reciprocal repression between mmu_-circ_0000730 and mmu-miR-466i-3p. We further showed that both mmu-miR-466i-3p and mmu-miR-466 f-3p suppresses a number of genes involved in epithelial-mesenchymal transition (EMT) and stemness of cancer stem cells such as SOX9. Conclusions: These results provide evidence of a previously unrecognized regulatory role of noncoding RNAs in microbiota-mediated cancer metastasis, and thus, the microbiome may serve as a therapeutic target.

Identification and Characterization of Circular RNA as a Novel Regulator and Biomarker in Preterm Birth

“…First, the sample size was small, so more samples are needed to confirm the predictive value of circRNAs for PTB. Second, the actual function of circRNA may be affected by the complex biological factors in pregnant women, for example, the level of oxidative stress may affect circRNA expression , and changes in gut microbes may affect the regulation of metabolic function by circRNA (Zhu et al, 2020), and these factors may vary widely among individuals. Therefore, we will carry out miRNA/mRNA-seq, molecular experiments, and animal experiments, to further exclude potential confounding factors and analyze the actual effect of circRNA on preterm delivery.…”

Gut microbiota of patients with different subtypes of gastric cancer and gastrointestinal stromal tumors

“…Moreover, only diffuse subtype had significantly low abundances of bacteria belonging to Bifidobacteriaceae family . Bifidobacterium, an important member of this family and widely used as probiotic, is reported to suppress metastasis in mouse model via its effect on IL-11 expression and subsequent effect on circRNA/microRNA/sox9 axis and epithelial-mesenchymal transition genes [ 19 ]. Abundance of gut Bifidobacterium is also associated with the accumulation of activated antigen-specific T cells in the tumor microenvironment and its low abundance is related to more aggressive tumors in mice [ 20 ].…”

miRNA-Based Potential Biomarkers and New Molecular Insights in Ulcerative Colitis

“…Moreover, nitric oxide can modify the S-nitrosylation of AGO proteins in mammals (Seth et al, 2019). In addition, the reduction of intestinal microbial community abundance in specific pathogen-free (SPF) mice mediated by broad-spectrum antibiotics promoted tumor lung metastasis through circRNA/miRNA networks, while tumor metastasis was effectively inhibited by transplantation of fecal bacteria into germ-free (GF) mice using SPF mice feces (Zhu et al, 2020a). Fusobacterium nucleatum inhibits the expression of miR-18a* and miR-4802 by activating the TLR4/MYD88 pathway.…”