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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

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

Authors: Ye Wang, Meijuan Wu, Zengjie Lei, Mengxi Huang, Zhiping Li, Liya Wang, Qijun Cao, Dong Han, Yue Chang, Yanyan Chen, Xiaobei Liu, Lijun Xue, Xiaobei Mao, Jian Geng, Yanan Chen, Tingting Dai, Lili Ren, Qian Wang, Hongju Yu, Cheng Chen, Xiaoyuan Chu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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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.
Appendix
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Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.CrossRef
2.
Chen W, Zheng R, Zeng H, Zhang S. The updated incidences and mortalities of major cancers in China, 2011. Chin J Cancer. 2015;34(11):502–7.PubMed
3.
4.
Chu XY, Zhu ZM, Chen LB, Wang JH, Su QS, Yang JR, Lin Y, Xue LJ, Liu XB, Mo XB. FOXM1 expression correlates with tumor invasion and a poor prognosis of colorectal cancer. Acta Histochem. 2012;114(8):755–62.CrossRef
5.
Xu K, Liu X, Mao X, Xue L, Wang R, Chen L, Chu X. MicroRNA-149 suppresses colorectal cancer cell migration and invasion by directly targeting forkhead box transcription factor FOXM1. Cell Physiol Biochem. 2015;35(2):499–515.CrossRef
6.
Liu X, Xie T, Mao X, Xue L, Chu X, Chen L. MicroRNA-149 increases the sensitivity of colorectal Cancer cells to 5-fluorouracil by targeting Forkhead box transcription factor FOXM1. Cell Physiol Biochem. 2016;39(2):617–29.CrossRef
7.
Xie T, Geng J, Wang Y, Wang L, Huang M, Chen J, Zhang K, Xue L, Liu X, Mao X, Chen Y, Wang Q, Dai T, Ren L, Yu H, Wang R. FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10. Oncotarget. 2017;8(5):8574–89.CrossRef
8.
He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.CrossRef
9.
Xiao F, Bai Y, Chen Z, Li Y, Luo L, Huang J, Yang J, Liao H, Guo L. Downregulation of HOXA1 gene affects small cell lung cancer cell survival and chemoresistance under the regulation of miR-100. Eur J Cancer. 2014;50(8):1541–54.CrossRef
10.
Bouchie A. First microRNA mimic enters clinic. Nat Biotechnol. 2013;31(7):577.CrossRef
11.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–22.CrossRef
12.
Bertoli G, Cava C, Castiglioni I. MicroRNAs: new biomarkers for diagnosis, prognosis, therapy prediction and therapeutic tools for breast Cancer. Theranostics. 2015;5(10):1122–43.CrossRef
13.
Wang Z, Banerjee S, Kong D, Li Y, Sarkar FH. Down-regulation of Forkhead box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. Cancer Res. 2007;67(17):8293–300.CrossRef
14.
Zhang Y, Zhang N, Dai B, Liu M, Sawaya R, Xie K, Huang S. FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells. Cancer Res. 2008;68(21):8733–42.CrossRef
15.
Li Q, Zhang N, Jia Z, Le X, Dai B, Wei D, Huang S, Tan D, Xie K. Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression. Cancer Res. 2009;69(8):3501–9.CrossRef
16.
Wang Z, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar FH. Forkhead box M1 transcription factor: a novel target for cancer therapy. Cancer Treat Rev. 2010;36(2):151–6.CrossRef
17.
Bella L, Zona S, Nestal de Moraes G, Lam EW. FOXM1: a key oncofoetal transcription factor in health and disease. Semin Cancer Biol. 2014;29:32–9.CrossRef
18.
Polytarchou C, Iliopoulos D, Struhl K. An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state. Proc Natl Acad Sci U S A. 2012;109(36):14470–5.CrossRef
19.
Rokavec M, Öner MG, Li H, Jackstadt R, Jiang L, Lodygin D, Kaller M, Horst D, Ziegler PK, Schwitalla S, Slotta-Huspenina J. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124(4):1853–67.CrossRef
20.
Taby R, Issa JPJ. Cancer epigenetics. CA Cancer J Clin. 2010;60(6):376–92.CrossRef
21.
Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286–98.CrossRef
22.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.CrossRef
23.
Kim SH, Joshi K, Ezhilarasan R, Myers TR, Siu J, Gu C, Nakano-Okuno M, Taylor D, Minata M, Sulman EP, Lee J, Bhat KP. EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Stem Cell Rep. 2015;4(2):226–38.CrossRef
24.
Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, Waghorn K, Zoi K, Ross FM, Reiter A, Hochhaus A. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42(8):722–6.CrossRef
25.
Martinez-Garcia E, Licht JD. Deregulation of H3K27 methylation in cancer. Nat Genet. 2010;42(2):100–1.CrossRef
26.
Li M, Yang J, Zhou W, Ren Y, Wang X, Chen H, Zhang J, Chen J, Sun Y, Cui L, Liu X, Wang L, Wu C. Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer. Br J Cancer. 2017;117(7):974–83.CrossRef
27.
Sanders DA, Ross-Innes CS, Beraldi D, Carroll JS, Balasubramanian S. Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells. Genome Biol. 2013;14(1):R6.CrossRef
28.
Xia L, Huang W, Tian D, Zhu H, Zhang Y, Hu H, Fan D, Nie Y, Wu K. Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. J Hepatol. 2012;57(3):600–12.CrossRef
29.
Wu XR, Chen YH, Liu DM, Sha JJ, Xuan HQ, Bo JJ, Huang YR. Increased expression of forkhead box M1 protein is associated with poor prognosis in clear cell renal cell carcinoma. Med Oncol. 2013;30(1):346.CrossRef
30.
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.CrossRef
31.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27–31.CrossRef
32.
Alfaro C, Sanmamed MF, Rodríguez-Ruiz ME, Teijeira Á, Oñate C, González Á, Ponz M, Schalper KA, Pérez-Gracia JL. Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat Rev. 2017;60:24–31.CrossRef
33.
Gong L, Cumpian AM, Caetano MS, Ochoa CE, De la Garza MM, Lapid DJ, Mirabolfathinejad SG, Dickey BF, Zhou Q, Moghaddam SJ. Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase. Mol Cancer. 2013;12(1):15.CrossRef
34.
Lee YS, Choi I, Ning Y, Kim NY, Khatchadourian V, Yang D, Chung HK, Choi D, LaBonte MJ, Ladner RD, Nagulapalli Venkata KC. Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis. Br J Cancer. 2012;106(11):1833–41.CrossRef
35.
Lim EL, Trinh DL, Ries RE, Wang J, Gerbing RB, Ma Y, Topham J, Hughes M, Pleasance E, Mungall AJ, Moore R, Zhao Y. MicroRNA expression-based model indicates event-free survival in pediatric acute myeloid leukemia. J Clin Oncol. 2017;35(35):3964–77.CrossRef
36.
Bagnoli M, Canevari S, Califano D, Losito S, Maio MD, Raspagliesi F, Carcangiu ML, Toffoli G, Cecchin E, Sorio R. Development and validation of a microRNA-based signature (MiROvaR) to predict early relapse or progression of epithelial ovarian cancer: a cohort study. Lancet Oncol. 2016;17(8):1137–46.CrossRef
37.
Esposito CL, Nuzzo S, Kumar SA, Rienzo A, Lawrence CL, Pallini R, Shaw L, Alder JE, Ricci-Vitiani L, Catuogno S. A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells. J Control Release. 2016;238:43–57.CrossRef
38.
Shu D, Li H, Shu Y, Xiong G, Carson WE, Haque F, Xu R, Guo P. Systemic delivery of anti-miRNA for suppression of triple negative breast Cancer utilizing RNA nanotechnology. ACS Nano. 2015;9(10):9731–40.CrossRef
39.
Chen Y, Gao DY, Huang L. In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev. 2015;81:128–41.CrossRef
40.
Sibley CR, Seow Y, Saayman S, Dijkstra KK, El Andaloussi S, Weinberg MS, Wood MJ. The biogenesis and characterization of mammalian microRNAs of mirtron origin. Nucleic Acids Res. 2012;40(1):438–48.CrossRef
41.
Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128–34.CrossRef
42.
Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, Woodward WA, Hsu JM, Hortobagyi GN, Hung MC. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell. 2011;19(1):86–100.CrossRef
43.
Ren G, Baritaki S, Marathe H, Feng J, Park S, Beach S, Bazeley PS, Beshir AB, Fenteany G, Mehra R, Daignault S. Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res. 2012;72(12):3091–104.CrossRef
44.
Taniguchi H, Jacinto FV, Villanueva A, Fernandez AF, Yamamoto H, Carmona FJ, Puertas S, Marquez VE, Shinomura Y. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2012;31(15):1988–94.CrossRef
Metadata
Title
Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis
Authors
Ye Wang
Meijuan Wu
Zengjie Lei
Mengxi Huang
Zhiping Li
Liya Wang
Qijun Cao
Dong Han
Yue Chang
Yanyan Chen
Xiaobei Liu
Lijun Xue
Xiaobei Mao
Jian Geng
Yanan Chen
Tingting Dai
Lili Ren
Qian Wang
Hongju Yu
Cheng Chen
Xiaoyuan Chu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0970-5

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