A deeper mechanistic understanding of tumour angiogenesis regulation is needed to improve current anti-angiogenic therapies. Here we present evidence from systems-based miRNA analyses of large-scale patient data sets along with in vitro and in vivo experiments that miR-192 is a key regulator of angiogenesis. The potent anti-angiogenic effect of miR-192 stems from its ability to globally downregulate angiogenic pathways in cancer cells through regulation of EGR1 and HOXB9. Low miR-192 expression in human tumours is predictive of poor clinical outcome in several cancer types. Using 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoliposomes, we show that miR-192 delivery leads to inhibition of tumour angiogenesis in multiple ovarian and renal tumour models, resulting in tumour regression and growth inhibition. This anti-angiogenic and anti-tumour effect is more robust than that observed with an anti-VEGF antibody. Collectively, these data identify miR-192 as a central node in tumour angiogenesis and support the use of miR-192 in an anti-angiogenesis therapy.
Bibliographical noteFunding Information:
S.Y.W. is supported by the Ovarian Cancer Research Fund Alliance, Foundation for Womens Cancer, Texas Center for Cancer Nanomedicine and the Cancer Prevention Research Institute of Texas training grants (RP101502 and RP101489). R.R. is supported by the Russell and Diana Hawkins Family Foundation Discovery Fellowship. F.S. is supported by the Jiangsu Health International Exchange Program Fellowship. S.P. and G.N.A.-P. are supported by the Foundation for Womens Cancer. C.V.P. was supported by the NCI T32 training grant CA009666. E.P. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research and a Trainee Travel Award from Ovarian Cancer Canada. M.H. is supported by the Deutsche Forschungsgemeinschaft Research Fellowship. L.J.N.C. has ownership interests at Intrexon, Targazyme and Ziopharm; has patents with Sangamo BioSciences, reports receiving speakers bureau honoraria from Miltenyi; is a consultant/advisory board member for Ferring Pharmaceuticals and GE Healthcare; and reports receiving commercial research grants from Immatics US. Portions of this work were supported by the NIH (GM100777-01, GM086937-01, GM084552-04, CA016672, CA109298, P50 CA083639, P50 CA098258, CA128797, U54 CA151668, UH2 TR000943, U24CA143835 and P30CA16672), NCI-DHHS-NIH T32 Training grant (T32 CA101642), the DOD (OC120547 and OC093416), the Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), the Blanton-Davis Ovarian Cancer Research Program, the RGK Foundation, the Gilder Foundation and the Betty Anne Asche Murray Distinguished Professorship. STR DNA fingerprinting was done by the Cancer Center Support Grant-funded Characterized Cell Line core, NCI CA016672. We thank D. Ruder, D. Reynolds, J. Seymour, Drs T. Miyake, T. Hisamatsu, R. Langley and the members of the histology and flow cytometry facilities at the University of Texas M.D. Anderson Cancer Center for technical assistance.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)