&amp;lt;italic&amp;gt;BMPRII&amp;lt;/italic&amp;gt; is a direct target of miR-21

Qin, Wenming; Zhao, Bingjie; Shi, Yi; Yao, Chengguo; Jin, Li; Jin, Youxin

doi:10.1093/abbs/gmp049

Cited by 56 publications

(32 citation statements)

References 32 publications

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“…First, bioinformatics predictions suggested that PTX3, HAS2 and PTGS2 are not the target genes of miR-375, and miR-375/ BMPR2 does not directly regulate PTX3, HAS2, and PTGS2. The reason for decreased levels of PTX3, HAS2 and PTGS2 may be because miR-375 triggers a large number of cells to undergo apoptosis, which is also supported by some previous reports [17, 19, 25] and our follow-up experiments (Fig. 7).…”

Section: Discussionsupporting

confidence: 91%

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Liu¹,

Yuan²,

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), which are secreted by oocytes, are important regulators of follicular growth and development and ovarian function. These two factors can regulate the proliferation and apoptosis of cumulus cells via modulation of the Smad signaling pathway. Studies have shown that BMP15 and GDF9 can affect the level of miR-375, whereas the target gene of miR-375 is BMPR2, the type II receptor of BMP15 and GDF9. However, whether or how the BMP15/ GDF9-miR-375-BMPR2 pathway affects the proliferation and apoptosis of bovine cumulus cells through regulation of the Smad signaling pathway remains unclear. Methods: In this study, cumulus cells were first obtained from cumulus-oocyte complexes (COCs). Appropriate concentrations of BMP15 and GDF9 were added during the in vitro culture process. Cell Counting Kit-8 (CCK-8) analyses and flow cytometry were used to determine the effects of BMP15/GDF9 on bovine cumulus cells proliferation and apoptosis. Subsequently, miR-375 mimics, miR-375 inhibitor and BMPR2 siRNA were synthesized and used for transfection experiments. Western Blot analysis was used to detect changes before and after transfection in the expression levels of the BMP15/GDF9 type I receptors ALK4, ALK5 and ALK6; the phosphorylation levels of Smad2/3 and Smad1/5/8, which are key signaling pathway proteins downstream of BMP15/GDF9; the expression levels of PTX3, HAS2 and PTGS2, which are key genes involved in cumulus cells proliferation; and Bcl2/Bax, which are genes involved in apoptosis. Results: The addition of 100 ng/mL BMP15 or 200 ng/mL GDF9 or the combined addition of 50 ng/mL BMP15 and 100 ng/mL GDF9 effectively inhibited bovine cumulus cell apoptosis and promoted cell proliferation. BMP15/GDF9 negatively regulated miR-375 expression and positively regulated BMPR2 expression. High levels of miR-375 and inhibition of BMPR2 resulted in increased expression of ALK4 and decreased expression of PTX3, HAS2 and PTGS2, whereas miR-375 inhibition resulted in the opposite results. BMP15 and GDF9 significantly activated the levels of p-Smad2/3 and p-Smad1/5/8, whereas miR-375 inhibited the levels of p-Smad2/3 and p-Smad1/5/8 by negatively regulating BMPR2 and also led to apoptosis. Conclusion: BMP15 and GDF9 have synergistic effects and can act through miR-375 to affect the expression levels of type I receptor ALK4 and type II receptor BMPR2 and the activation of Smad signaling pathway, which subsequently affected the proliferation, spread and apoptosis of cumulus cells.

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Section: Discussionsupporting

confidence: 91%

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Liu¹,

Yuan²,

Chen³

et al. 2018

Cell Physiol Biochem

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“…These mutations prevent the activation of caspases-8, -9, and -3 and result in the derepression of Bcl2. In human prostate carcinoma cells, Qin et al [49] recently showed that through direct targeting of four predicted sites within BMPR2 mRNA, miR-21 down-regulates levels of BMPR2.…”

Section: Mir-21 Targetsmentioning

confidence: 99%

Apoptosis and the target genes of microRNA-21

Buscaglia¹,

Yong²

2011

Chin J Cancer

223

182

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MicroRNA-21 (miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors. Through functional suppression, miR-21 is implicated in practically every walk of oncogenic life: the promotion of cell proliferation, invasion and metastasis, genome instability and mutation, inflammation, replicative immortalization, abnormal metabolism, angiogenesis, and evading apoptosis, immune destruction, and growth suppressors. In particular, miR-21 is strongly involved in apoptosis. In this article, we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis. This suggests that miR-21 is an Oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.

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“…Specifically, miR-21 has been found to be overexpressed in numerous different solid tumors. Altered miR-21 has been found to be associated with the proliferation, invasion and apoptosis of malignant cells by targeting and downregulating a number of tumor suppressors, including PTEN (6,7), programmed cell death 4 (PDCD4) (8)(9)(10)(11), bcl-2 and tropomyosin l (TPM1) (12)(13), bone morphogenetic protein receptor II (BMPRII) (14) and sprouty 2 (SPRY2) (15). These findings imply that miR-21 plays a fundamental role in malignant behavior and transformation.…”

Section: Introductionmentioning

confidence: 99%

microRNA-21 overexpression contributes to cell proliferation by targeting PTEN in endometrioid endometrial cancer

et al. 2012

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Abstract. The aim of this study was to investigate the role of microRNA-21 (miR-21) in the regulation of phosphatase and tensin homolog deleted from chromosome-10 (PTEN) expression and proliferation of endometrioid endometrial cancer (EEC) cells. We performed a qRT-PCR assay with miR-21 and PTEN in 16 paired EEC tumor tissues and adjacent non-tumor endometrium. To investigate the regulation of PTEN by miR-21, we designed gain-and loss-of-function of miR-21 experiments in the KLE cell line by transfection with a synthetic miR-21 mimic and inhibitor. To validate the putative binding site of miR-21 in the 3' untranslated region (3'-UTR) of PTEN messenger RNA (mRNA), a dual-luciferase reporter assay was carried out. To evaluate the potential effect of miR-21 on EEC proliferation, we performed both overexpression experiments, using an miR-21 mimic, and inhibition assays, using an miR-21 inhibitor. miR-21 was overexpressed in EEC and was inversely correlated with PTEN protein expression (P<0.001). miR-21 regulated PTEN protein expression and cell proliferation in the KLE cell line and the direct binding of miR-21 to the PTEN 3'-UTR was confirmed using a dual-luciferase reporter assay. The upregulation of miR-21 led to a significant decrease in the PTEN protein expression level (P=0.007). The downregulation of miR-21 led to a significant increase in PTEN protein (P=0.002). The expression of luciferase in the wt-PTEN-3'-UTR-pGL3 group was downregulated in the presence of the miR-21 mimic (P=0.001). miR-21 was overexpressed in EEC. In conclusion, we demonstrated that the expression of PTEN protein, but not mRNA, was negatively directly regulated by miR-21 in the KLE cell line. The overexpression of miR-21 modulated EEC cell proliferation through the downregulation of PTEN.

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<italic>BMPRII</italic> is a direct target of miR-21

Cited by 56 publications

References 32 publications

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Apoptosis and the target genes of microRNA-21

microRNA-21 overexpression contributes to cell proliferation by targeting PTEN in endometrioid endometrial cancer

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