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Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2.

Tu Y, Liu L, Zhao D, Liu Y, Ma X, Fan Y, Wan L, Huang T, Cheng Z, Shen B - Sci Rep (2015)

Bottom Line: The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo.Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway.Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Imaging, College of Heilongjiang Province, Harbin, Heilongjiang, China.

ABSTRACT
Recent studies reported miR-497 exhibited inhibitory effects in various cancers. However, whether miR-497 is involved in inhibiting angiogenesis, which is critical for tumor growth and metastasis, is still unknown. The purpose of this study was to investigate the potential role of miR-497 in tumor angiogenesis. In this work, cell proliferation and apoptosis analyses were conducted to explore the potential function of miR-497 in HUVECs by using MTT and TUNEL assays. Western blotting (WB) was employed to validate the downstream targets of miR-497. Furthermore, in order to disclose the role of miR-497 on angiogenesis, VEGFR2-luc transgenic mice were treated with miR-497 mimic and applied to monitor tumor angiogenesis and growth by in vivo bioluminescent imaging (BLI). The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo. Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway. Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis. In summary, miR-497 inhibits tumor angiogenesis and growth via targeting VEGFR2, indicating miR-497 can be explored as a potential drug candidate for cancer therapy.

No MeSH data available.


Related in: MedlinePlus

Schematic illustrations explain the possible targeting and signalling mechanisms by which miR-497 produces anti-angiogenesis effects in in vitro and in vivo model.Increased miR-497 represses angiogenesis by targeting VEGFR2, which lead to decreases in the activation of both PI3K/AKT and Raf/MEK/ERK signaling pathways. In addition, miR-497 may induce endothelial cells apoptosis by directly down-regulating anti-apoptotic factor Bcl-2 expression. And this schematic diagram was drawn by Yingfeng Tu and Xiaowei Ma.
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f7: Schematic illustrations explain the possible targeting and signalling mechanisms by which miR-497 produces anti-angiogenesis effects in in vitro and in vivo model.Increased miR-497 represses angiogenesis by targeting VEGFR2, which lead to decreases in the activation of both PI3K/AKT and Raf/MEK/ERK signaling pathways. In addition, miR-497 may induce endothelial cells apoptosis by directly down-regulating anti-apoptotic factor Bcl-2 expression. And this schematic diagram was drawn by Yingfeng Tu and Xiaowei Ma.

Mentions: In this study, several novel findings have been disclosed. Firstly, we demonstrated, for the first time, that VEGFR2 was the target gene of miR-497, which could be down-regulated by overexpression of miR-497 in HUVECs and 4T1 breast cancer cells. Secondly, as shown in Fig. 7, up-regulation of miR-497 level was able to induce HUVECs apoptosis via targeting VEGFR2/PI3K/AKT signaling pathway and trigger anti-proliferative action through VEGFR2/Raf/ERK/MEK signaling pathway in HUVECs. Thirdly, overexpression of miR-497 produced anti-tumor and anti-angiogenesis effects in breast tumor-bearing mice, and VEGFR2-luc mouse was a useful tool in monitoring the therapeutic anti-angiogenesis effect of miR-497 in vivo. In brief, these results not only help us to comprehend the mechanisms underlying the anti-angiogenesis effects of miR-497 but also improve our view of miRNAs that may serve as potential therapeutic and drug targets in future.


Overexpression of miRNA-497 inhibits tumor angiogenesis by targeting VEGFR2.

Tu Y, Liu L, Zhao D, Liu Y, Ma X, Fan Y, Wan L, Huang T, Cheng Z, Shen B - Sci Rep (2015)

Schematic illustrations explain the possible targeting and signalling mechanisms by which miR-497 produces anti-angiogenesis effects in in vitro and in vivo model.Increased miR-497 represses angiogenesis by targeting VEGFR2, which lead to decreases in the activation of both PI3K/AKT and Raf/MEK/ERK signaling pathways. In addition, miR-497 may induce endothelial cells apoptosis by directly down-regulating anti-apoptotic factor Bcl-2 expression. And this schematic diagram was drawn by Yingfeng Tu and Xiaowei Ma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561885&req=5

f7: Schematic illustrations explain the possible targeting and signalling mechanisms by which miR-497 produces anti-angiogenesis effects in in vitro and in vivo model.Increased miR-497 represses angiogenesis by targeting VEGFR2, which lead to decreases in the activation of both PI3K/AKT and Raf/MEK/ERK signaling pathways. In addition, miR-497 may induce endothelial cells apoptosis by directly down-regulating anti-apoptotic factor Bcl-2 expression. And this schematic diagram was drawn by Yingfeng Tu and Xiaowei Ma.
Mentions: In this study, several novel findings have been disclosed. Firstly, we demonstrated, for the first time, that VEGFR2 was the target gene of miR-497, which could be down-regulated by overexpression of miR-497 in HUVECs and 4T1 breast cancer cells. Secondly, as shown in Fig. 7, up-regulation of miR-497 level was able to induce HUVECs apoptosis via targeting VEGFR2/PI3K/AKT signaling pathway and trigger anti-proliferative action through VEGFR2/Raf/ERK/MEK signaling pathway in HUVECs. Thirdly, overexpression of miR-497 produced anti-tumor and anti-angiogenesis effects in breast tumor-bearing mice, and VEGFR2-luc mouse was a useful tool in monitoring the therapeutic anti-angiogenesis effect of miR-497 in vivo. In brief, these results not only help us to comprehend the mechanisms underlying the anti-angiogenesis effects of miR-497 but also improve our view of miRNAs that may serve as potential therapeutic and drug targets in future.

Bottom Line: The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo.Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway.Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Imaging, College of Heilongjiang Province, Harbin, Heilongjiang, China.

ABSTRACT
Recent studies reported miR-497 exhibited inhibitory effects in various cancers. However, whether miR-497 is involved in inhibiting angiogenesis, which is critical for tumor growth and metastasis, is still unknown. The purpose of this study was to investigate the potential role of miR-497 in tumor angiogenesis. In this work, cell proliferation and apoptosis analyses were conducted to explore the potential function of miR-497 in HUVECs by using MTT and TUNEL assays. Western blotting (WB) was employed to validate the downstream targets of miR-497. Furthermore, in order to disclose the role of miR-497 on angiogenesis, VEGFR2-luc transgenic mice were treated with miR-497 mimic and applied to monitor tumor angiogenesis and growth by in vivo bioluminescent imaging (BLI). The results demonstrated that overexpression of miR-497 showed inhibitory effects on VEGFR2 activation and downstream Raf/MEK/ERK signal pathways in vitro and in vivo. Moreover, overexpression of miR-497 effectively induced HUVECs apoptosis by targeting VEGFR2 and downstream PI3K/AKT signaling pathway. Furthermore, miR-497 exhibited anti-angiogenesis and anti-tumor effects in the VEGFR2-luc breast tumor model proven by BLI, WB and immunohistochemistry analysis. In summary, miR-497 inhibits tumor angiogenesis and growth via targeting VEGFR2, indicating miR-497 can be explored as a potential drug candidate for cancer therapy.

No MeSH data available.


Related in: MedlinePlus