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


ABSTRACT:

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.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC6264626 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Wang Ye Y   Wu Meijuan M   Lei Zengjie Z   Huang Mengxi M   Li Zhiping Z   Wang Liya L   Cao Qijun Q   Han Dong D   Chang Yue Y   Chen Yanyan Y   Liu Xiaobei X   Xue Lijun L   Mao Xiaobei X   Geng Jian J   Chen Yanan Y   Dai Tingting T   Ren Lili L   Wang Qian Q   Yu Hongju H   Chen Cheng C   Chu Xiaoyuan X  

Journal of experimental & clinical cancer research : CR 20181128 1


<h4>Background</h4>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.<h4>Methods</h4>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  ...[more]

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