Abstract
BackgroundTranscription 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.MethodsDual-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.ResultsThrough 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.ConclusionsTogether, 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.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer-related death in the world [1]
forkhead box M1 (FOXM1) is negatively regulated by miR-6868-5p To explore potential miRNAs in the regulation of FOXM1, we used four different bio-informatic prediction tools to analyze if miRNA-binding sites are present in the FOXM1 3′-untranslated region (3’-UTR) region and identified 13 miRNAs from intersection (Fig. 1a)
By detecting the endogenous expression of miR-6868-5p and three other miRNAs that have been reported to function in colorectal cancer (CRC) cells, we found that miR-6868-5p level was comparable to the other three miRNAs (Additional file 1: Figure S1A)
Summary
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer-related death in the world [1]. The incidence and mortality of CRC has increased rapidly in China [2]. The development and progression of CRC is regulated by various genetic and epigenetic manners. Forkhead box M1 (FOXM1) is a transcription factor that belongs to the FOX superfamily, characterized by a conserved winged helix DNA-binding domain [3]. FOXM1 is frequently overexpressed in a variety of cancers, including CRC. Our previous studies have shown that FOXM1 expression predicted poor prognosis of. Transcription factor forkhead box M1 (FOXM1) is a crucial regulator in colorectal cancer (CRC) progression. The regulatory mechanisms causing dysregulation of FOXM1 in CRC remain unclear
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