Abstract
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 non-coding RNAs in microbiota-mediated cancer metastasis, and thus, the microbiome may serve as a therapeutic target.
Highlights
We observed the visible differences in the number of metastatic nodules between specific pathogen-free (SPF) and SPF/ABX (SPF mice with broad-antibiotics administration) mice (Figure 1B-F)
We found that Fecal microbiota transplantation (FMT) from SPF mice or Bifidobacterium into germfree (GF) avatar mice inhibited tumor metasta sis
The integrity of gut microbiota or Probiotics Bifidobacterium is favorable in anti-cancer therapy,[40,41] cancer patients often take ABX generally for common indications,[42,43] or take ABX during the perioperative period, or because of diagnostic treatment in order to exclude infection before the definite diagnosis
Summary
Gut microbiota has been implicated in cancer.[1,2] Evidence is growing that the gut microbiota mod ulates the host response to cancer therapeutics, such as primary resistance to chemotherapy or immunotherapy.[3,4,5,6,7] gut microbiota dys biosis due to broad-spectrum antibiotics (ABX) during anticancer treatments may disturb the can cer microenvironment contributing to cancer progression.[8,9,10] little is known about whether gut microbiota regulates tumor metastasis.Metastasis is a complex process that requires the interaction between tumor cells and their microenvironment.[11]. Gut microbiota has been implicated in cancer.[1,2] Evidence is growing that the gut microbiota mod ulates the host response to cancer therapeutics, such as primary resistance to chemotherapy or immunotherapy.[3,4,5,6,7] gut microbiota dys biosis due to broad-spectrum antibiotics (ABX) during anticancer treatments may disturb the can cer microenvironment contributing to cancer progression.[8,9,10] little is known about whether gut microbiota regulates tumor metastasis. Little is known as to whether gut microbiota alters the tumor microenvironment by affecting cir culating non-coding RNAs such as circular RNAs (circRNAs)/microRNAs (miRNAs) that contribute to cancer metastasis; and the underlying mechanism remains to be determined yet. We report that broad-spectrum antibiotics (ABX) treatment leads to enhanced metastasis by the alteration of gut microbiome composition. Conclusions: These results provide evidence of a previously unrecognized regulatory role of noncoding RNAs in microbiota-mediated cancer metastasis, and the microbiome may serve as a therapeutic target
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