A miR-192-EGR1-HOXB9 regulatory network controls the angiogenic switch in cancer

Abstract

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.

The role of MicroRNA molecules and MicroRNA-regulating machinery in the pathogenesis and progression of epithelial ovarian cancer

“…AntagomiR MiR-1307 treatment of mice with xenograft tumors resulted in a decrease in tumor size and an even further decrease in tumor size with paclitaxel treatment (66). Treatment of xenograft mouse models with miR-192-DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) leads to inhibition of angiogenesis and tumor growth (67). MiR-551b-3p is located in a genomic region frequently amplified in high-grade serous EOC (68).…”

Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy

“…To identify miRs with altered expression in tumor vasculature, we isolated ECs from human tissue samples of high-grade serous ovarian cancer (n = 3) and normal ovarian tissues (n = 3) and performed nanostring analysis (7). Array results showed that 5 miRs were markedly upregulated and 7 miRs were downregulated in ovarian tumor ECs compared with normal ECs (Supplemental Table 1; supplemental material available online with this article; doi:10.1172/jci.insight.87754DS1).…”

“…MicroRNAs (miRs) have been shown to play a vital role in tumor development and angiogenic processes by modulating the expression of critical angiogenesis factors (7). Deregulation of miRs has been identified in many cancer types and is closely related to tumor progression and metastasis.…”

Tumor Microenvironment and Models of Ovarian Cancer

“…He reported that there are a number of barriers to the delivery of miRNAs to ovarian cancer tumors, 6 including the finding that hypoxia downregulates the miRNA processing machinery including DICER. 7 Dr Sood's group has found that miR-192 is antiangiogenic 8 and is now optimizing delivery strategies including nanoparticle and thioaptamer approaches. These efforts are now in phase I clinical trials at MD Anderson.…”