Gut microbiota regulate tumor metastasis via circRNA/miRNA networks.
Gut microbiota regulate tumor metastasis via circRNA/miRNA networks.
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肠道微生物群通过 circRNA/miRNA 网络调节肿瘤转移
DOI：
10.1080/19490976.2020.1788891
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发表时间：
2020-11-09
期刊：
影响因子：
12.2
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Zhu Z;Huang J;Li X;Xing J;Chen Q;Liu R;Hua F;Qiu Z;Song Y;Bai C;Mo YY;Zhang Z
摘要背景越来越多的证据表明，肠道微生物群在癌症进展中起着重要作用。然而，其潜在的机制在很大程度上仍不清楚。在这里，我们报告了广谱抗生素（ABX）治疗通过改变肠道微生物组组成而导致转移增强。方法采用小鼠肿瘤LLC和B16-F10细胞转移模型，通过微阵列/RNA测序分析，揭示微生物群介导的环状RNA（circRNA）/microRNA（miRNA）网络在肿瘤转移中的调控作用。结果ABX处理的SPF小鼠肺转移明显增强。SPF小鼠或双歧杆菌属的粪便微生物群移植（FMT）到无菌小鼠中显著抑制肺转移。从机制上讲，肠道微生物群影响circRNA表达，以调节相应的miRNA水平。具体地，肠道微生物群的这种调节以IL-11依赖性方式抑制mmu_circ_0000730表达。结合荧光素酶报告基因分析的生物信息学分析揭示了mmu_circ_0000730和mmu-miR-466 i-3 p之间的相互抑制。我们进一步表明mmu-miR-466 i-3 p和mmu-miR-466 f-3 p均抑制了参与上皮-间充质转化（EMT）和癌症干细胞的干细胞性（stemness）的许多基因，如SOX 9。结论这些结果提供了以前未被认识到的非编码RNA在微生物介导的癌症转移中的调节作用的证据，因此，微生物组可以作为治疗靶点。
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.
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