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Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis

BACKGROUND: Transcription factor forkhead box M1 (FOXM1) is a crucial regulator in colorectal cancer (CRC) progression. However, the regulatory mechanisms causing dysregulation of FOXM1 in CRC remain unclear. METHODS: Dual-luciferase reporter assay was conducted to determine FOXM1 as miR-6868-5p tar...

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Detalles Bibliográficos
Autores principales: Wang, Ye, Wu, Meijuan, Lei, Zengjie, Huang, Mengxi, Li, Zhiping, Wang, Liya, Cao, Qijun, Han, Dong, Chang, Yue, Chen, Yanyan, Liu, Xiaobei, Xue, Lijun, Mao, Xiaobei, Geng, Jian, Chen, Yanan, Dai, Tingting, Ren, Lili, Wang, Qian, Yu, Hongju, Chen, Cheng, Chu, Xiaoyuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264626/
https://www.ncbi.nlm.nih.gov/pubmed/30486864
http://dx.doi.org/10.1186/s13046-018-0970-5
Descripción
Sumario:BACKGROUND: Transcription factor forkhead box M1 (FOXM1) is a crucial regulator in colorectal cancer (CRC) progression. However, the regulatory mechanisms causing dysregulation of FOXM1 in CRC remain unclear. METHODS: Dual-luciferase reporter assay was conducted to determine FOXM1 as miR-6868-5p target. The function of miR-6868-5p and FOXM1 in CRC angiogenesis was verified in vitro. Intratumoral injection model was constructed to explore the effect of miR-6868-5p on angiogenesis in vivo. Chromatin immunoprecipitation assays were used to assess direct binding of H3K27me3 to the miR-6868 promoter. RESULTS: Through integrated analysis, we identified miR-6868-5p as the potent regulator of FOXM1. Overexpression of miR-6868-5p in CRC cells inhibited the angiogenic properties of co-cultured endothelial cells, whereas silencing of miR-6868-5p had opposite effects. In vivo delivery of miR-6868-5p blocked tumor angiogenesis in nude mice, resulting in tumor growth inhibition. Rescue of FOXM1 reversed the effect of miR-6868-5p on tumor angiogenesis. Further mechanistic study revealed that FOXM1 promoted the production of IL-8, which was responsible for the miR-6868-5p/FOXM1 axis-regulated angiogenesis. Reciprocally, FOXM1 inhibited miR-6868-5p expression through EZH2-mediated H3K27me3 on miR-6868-5p promoter, thus forming a feedback circuit. Clinically, the level of miR-6868-5p was downregulated in CRC tissues and inversely correlated with microvessel density as well as levels of FOXM1 and IL-8 in tumor specimens. CONCLUSIONS: Together, these data identify miR-6868-5p as a novel determinant of FOXM1 expression and establish a miR-6868-5p/FOXM1 regulatory circuit for CRC angiogenesis, providing potential target for CRC treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0970-5) contains supplementary material, which is available to authorized users.