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See detailEvidence for a role of microRNA-21 and microRNA-125b in negatively regulating angiogenic processes
Malvaux, Ludovic ULg

Doctoral thesis (2011)

Recently discovered, miRNAs have quickly become strong regulators of biological processes. These small non-coding RNAs of about 22 nucleotides partially base pair to the 3’UTR of the targeted mRNAs and ... [more ▼]

Recently discovered, miRNAs have quickly become strong regulators of biological processes. These small non-coding RNAs of about 22 nucleotides partially base pair to the 3’UTR of the targeted mRNAs and repress them. Due to their wide range effects, microRNAs were extensively studied in various diseases and were rapidly demonstrated to be deregulated in pathologies such as cancer. More recently, they have been shown to be implicated in vascular network formation (angiogenesis) and were proposed to be used in anti-angiogenic therapies. Nowadays about twenty angiomiRs have been discovered including the endothelial specific miR-126. As observed in several miRNA profiling of endothelial cells and confirmed in our laboratory in HUVECs (human umbilical veins endothelial cells), miR-21 and miR- 125b are highly expressed in this cell type suggesting that these miRNAs could play a role in vascular network formation. We then studied the implication of miR-21 and miR-125b in in vitro as well as in vivo angiogenesis. One of the most studied miRNA in cancer progression is miR-21 as it was shown to modify proliferating properties of numerous tumor cells. Our experiments revealed that miR-21 overexpression and inhibition have no direct effect on endothelial cells proliferation rate. However, miR-21 overexpression leads to the inhibition of HUVECs migration and tube formation as demonstrated in in vitro angiogenic assays. Moreover, opposite effects were observed upon miR-21 inhibition. We also confirmed that RhoB, a small Rho-GTPase implicated in stress fibers formation, is involved in these phenomena as RhoB inhibition using siRNA mimics miR-21 overexpression in endothelial cells. Moreover, miR-21 modulation affects RhoB mRNA and protein expressions. We further demonstrated a direct interaction between miR-21 and the RhoB 3’UTR confirming that miR-21 modulates angiogenesis partially through its effect on RhoB expression. A similar approach was used to study the implication of miR-125b in vascular network formation. In vivo, miR-125b expression was modulated in the zebrafish revealing that miR-125b expression needs to be controlled for proper intersomitic blood vessels establishment. In vitro, miR-125b overexpression decreases HUVECs migration and tube formation whereas miR-125b inhibition increases these functions. A transcriptomic analysis suggests that numerous adhesion molecules such as VE-cadherin or MCAM are involved in these processes. Furthermore, other proteins known to regulate angiogenesis such as the transcription factor ETS1 and the VEGFA receptor, VEGFR2 were also shown to be regulated by miR-125b. This observation confirms that miR-125b modulates angiogenic properties of endothelial cells. Finally, we investigated the impact of miR-21 and miR-125b overexpression in an in vivo pathological model of angiogenesis. In a mouse model of choroïdal neovascularization we demonstrated that miR-21 or miR-125b overexpression in the eyes of these mice decreases blood vessel establishment suggesting that these microRNAs could be used as therapeutic antiangiogenic agents. Taken together, the results presented in this thesis show that miR-21 and miR-125b regulate angiogenesis in vitro and in vivo. [less ▲]

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See detailMicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial Cells.
Sabatel, Céline; Malvaux, Ludovic ULg; Bovy, Nicolas ULg et al

in PLoS ONE (2011), 6(2), 16979

BACKGROUND: MicroRNAs (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 ... [more ▼]

BACKGROUND: MicroRNAs (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 FINDINGS: We 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/SIGNIFICANCE: Our results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB. [less ▲]

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See detailSprouty1, a new target of the angiostatic agent 16K prolactin, negatively regulates angiogenesis
Sabatel, Céline ULg; Cornet, Anne ULg; Tabruyn, Sébastien ULg et al

in Molecular Cancer (2010), 9(1), 231

BACKGROUND:Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future ... [more ▼]

BACKGROUND:Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future anti-cancer therapies. Sprouty1 (SPRY1), an inhibitor of the MAPK pathway, might be one of these new genes. We identified SPRY1 by comparing the transcriptomes of untreated endothelial cells with those of endothelial cells treated by the angiostatic agent 16K prolactin (16K hPRL). In the present study, we aimed to explore the potential function of SPRY1 in angiogenesis.RESULTS:We confirmed 16K hPRL induced up-regulation of SPRY1 in primary endothelial cells. In addition, we demonstrated the positive SPRY1 regulation in a chimeric mouse model of human colon carcinoma in which 16K hPRL treatment was shown to delay tumor growth. Expression profiling by qRT-PCR with species-specific primers revealed that induction of SPRY1 expression by 16K hPRL occurs only in the (murine) endothelial compartment and not in the (human) tumor compartment. The regulation of SPRY1 expression was NF-kappaB dependent. Partial SPRY1 knockdown by RNA interference protected endothelial cells from apoptosis as well as increased endothelial cell proliferation, migration, capillary network formation, and adhesion to extracellular matrix proteins. SPRY1 knockdown was also shown to affect the expression of cyclinD1 and p21 both involved in cell-cycle regulation. These findings are discussed in relation to the role of SPRY1 as an inhibitor of ERK/MAPK signaling and to a possible explanation of its effect on cell proliferation.CONCLUSIONS:Taken together, these results suggest that SPRY1 is an endogenous angiogenesis inhibitor. [less ▲]

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See detailThe angiostatic 16K human prolactin overcomes endothelial cell anergy and promotes leukocyte infiltration via nuclear factor-kappaB activation
Tabruyn, Sébastien ULg; Sabatel, Céline ULg; Nguyen, Ngoc-Quynh-Nhu ULg et al

in Molecular Endocrinology (2007), 21(6), 1422-9

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent angiostatic factor that inhibits tumor growth in mouse models. Using microarray experiments, we have dissected how the endothelial ... [more ▼]

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent angiostatic factor that inhibits tumor growth in mouse models. Using microarray experiments, we have dissected how the endothelial-cell genome responds to 16K hPRL treatment. We found 216 genes that show regulation by 16K hPRL, of which a large proportion turned out to be associated with the process of immunity. 16K hPRL induces expression of various chemokines and endothelial adhesion molecules. These expressions, under the control of nuclear factor-kappaB, result in an enhanced leukocyte-endothelial cell interaction. Furthermore, analysis of B16-F10 tumor tissues reveals a higher expression of adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, or E-selectin) in endothelial cells and a significantly higher number of infiltrated leukocytes within the tumor treated with 16K hPRL compared with the untreated ones. In conclusion, this study describes a new antitumor mechanism of 16K hPRL. Because cellular immunity against tumor cells is a crucial step in therapy, the discovery that treatment with 16K hPRL overcomes tumor-induced anergy may become important for therapeutic perspectives. [less ▲]

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