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

  • J Exp Clin Cancer Res. 2018 Nov 28;37(1):292. doi: 10.1186/s13046-018-0970-5.
Ye Wang  1 ,  Meijuan Wu  2 ,  Zengjie Lei  2 ,  Mengxi Huang  2 ,  Zhiping Li  1 ,  Liya Wang  2 ,  Qijun Cao  1 ,  Dong Han  1 ,  Yue Chang  2 ,  Yanyan Chen  2 ,  Xiaobei Liu  2 ,  Lijun Xue  2 ,  Xiaobei Mao  2 ,  Jian Geng  2 ,  Yanan Chen  2 ,  Tingting Dai  2 ,  Lili Ren  2 ,  Qian Wang  2 ,  Hongju Yu  2 ,  Cheng Chen  3  4 ,  Xiaoyuan Chu  5  6
Affiliations
  • 1. Departments of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, China.
  • 2. Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China.
  • 3. Departments of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, China. [email protected].
  • 4. Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China. [email protected].
  • 5. Departments of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, Jiangsu Province, China. [email protected].
  • 6. Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China. [email protected].
PMID: 30486864 DOI: 10.1186/s13046-018-0970-5
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.

Keywords
Angiogenesis; Colorectal cancer; FOXM1; miRNA.
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