MicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial Cells

Abstract

BackgroundMicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated.Methodology/Principal FindingsWe first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization.Conclusions/SignificanceOur results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB.

Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice

“…A proof-of-principle is shown in a MicroRNA (miRNA) study demonstrating CNV reduction through pre-miR administration (e.g. miR21, a miR with anti-angiogenic activity) 13 (Fig. 6).…”

“…The model has proven to be suitable for testing the efficacy of new drugs through systemic or local (intraocular) administration and has shown predictive value for drug effects in patients with AMD, for example with VEGFRtrap 9, 10 or anecortave acetate 11,12 . This model is also appropriate for identifying new potential targets using siRNA/miRNA technology 13 .…”

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

“…This is not surprising, as several of the key molecular regulators of angiogenesis, such as VEGFs, are also common to lymphangiogenesis during inflammation (1). miR-21, which has been shown to be both anti-and proangiogenic (33,52), is significantly upregulated in LECs in response to TNF-␣ ( Table 1). Results of the latter study (52) are consistent with our findings that miR-21 mimics reduced tube formation in LECs (Fig.…”

“…miR-21, which has been shown to be both anti-and proangiogenic (33,52), is significantly upregulated in LECs in response to TNF-␣ ( Table 1). Results of the latter study (52) are consistent with our findings that miR-21 mimics reduced tube formation in LECs (Fig. 4, A and B), suggesting an antilymphangiogenic role.…”

Identification of Serum MicroRNA-21 as a Biomarker for Early Detection and Prognosis in Human Epithelial Ovarian Cancer

“…When transfected with anti-miR-21, cell growth of breast cancer cell line MCF7 was inhibited, partly owing to the downregulation of Bcl-2 (Si et al, 2007). By targeting RhoB expression, microRNA-21 exhibited antiangiogenic function in endothelial cells (Sabatel et al, 2011). Furthermore, some other tumor related genes, such as PTEN, MARCKS, maspin, Cdc25A, and TMP1 have also been proven regulated by microRNA-21 in recent studies, However, an average miRNA can have more than 100 targets (Brennecke et al, 2005).…”