The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9

Hu, Jianzhong; Ni, Shuangfei; Cao, Yong; Zhang, Tao; Wu, Tianding; Yin, Xianzhen; Lang, Ye; Lü, Hongbin

doi:10.1371/journal.pone.0149537

Cited by 71 publications

(64 citation statements)

References 53 publications

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“…A previous report has indicated that the angiogenic effect of miR-21 acts by targeting TIMP3/MMP signaling 20 . Moreover, TIMP3/MMP9 signaling plays an important role in regulating vascular permeability 21 , 22 .…”

Section: Resultsmentioning

confidence: 99%

Exposure to Concentrated Ambient Fine Particulate Matter Induces Vascular Endothelial Dysfunction via miR-21

Dai

Chen²,

Lin³

et al. 2017

Int. J. Biol. Sci.

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Vascular endothelial permeability transition does not cause significant lesions, but enhanced permeability may contribute to the development of vascular and other diseases, including atherosclerosis, hypertension, heart failure and cancer. Therefore, elucidating the effect of Particulate Matter 2.5 (PM2.5) on vascular endothelial permeability could help prevent disease that might be caused by PM2.5. Our previous study and the present one revealed that PM2.5 significantly increased the permeability of vascular endothelial cells and disrupted the barrier function of the vascular endothelium in Sprague Dawley (SD) rats. We found that the effect occurred mainly through induction of signal transducer and activator of transcription 3 (STAT3) phosphorylation, further transcriptional regulation of microRNA21 (miR-21) and promotion of miR-21 expression. These changes post-transcriptionally repress tissue inhibitor of metalloproteinases 3 (TIMP3) and promote matrix metalloproteinases 9 (MMP9) expression. This work provides evidence that PM2.5 exerts direct inhibitory action on vascular endothelial barrier function and might give rise to a number of vascular diseases.

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Section: Resultsmentioning

confidence: 99%

Exposure to Concentrated Ambient Fine Particulate Matter Induces Vascular Endothelial Dysfunction via miR-21

Dai

Chen²,

Lin³

et al. 2017

Int. J. Biol. Sci.

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“…The expression of miR-126-5p enhances angiogenesis by repressing the expression of Spred-1, an intracellular inhibitor of angiogenic signaling, leading to enhanced signaling of angiogenic growth factors including VEGF and FGF 33 . MiR-21-5p promote angiogenesis partly through directly targeting TIMPs leading to enhanced VEGF signaling and endothelial cell migration 34 . Together with our observation of reduced expression of VEGF and FGF-β in tumor tissues, it suggests that an anti-angiogenic activity may be involved in the tumor inhibitory effect of Arc.…”

Section: Discussionmentioning

confidence: 99%

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

Wang

Solorzano

Diaz

et al. 2017

Clinical Nutrition Experimental

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The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its translation to human application.

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“…TIMP-3 is sequestered to ECMs, whereas all other TIMPs (TIMP-1, 2, and 4) are present in the soluble forms (Baker et al, 2002). Previous studies have been shown that TIMP-3 regulates the activities of MMPs, such as MMP-2, -7, -9, and -13 (Deb et al, 2015;Fu et al, 2016;Hu et al, 2016;Yamamoto et al, 2016). Herein, we also showed that S1P inhibits cell migration mainly by downregulation of MMP-2, but partially by MMP-7, -9, and -13.…”

Section: Discussionmentioning

confidence: 99%

“…3.3. S1P induces TIMP-3 expression through downregulation of microRNA (miRNA)-101 expression in human chondrosarcoma cells MicroRNA (miRNA) was shown to play important roles in the regulation of cancer progression and metastasis (Chen et al, 2015a;Hu et al, 2016;Nugent, 2015;Tsai et al, 2015). To investigate whether miRNA is responsible for the S1P-induced TIMP-3 expression, 12 predicted miRNA that contain binding sites of the 3 0 UTR of TIMP-3, identified by Targetscan (http://www.targetscan.org/), were studied.…”

Section: S1p Inhibits Mmp-2 Expression Through the Upregulation Of Timentioning

confidence: 99%

Sphingosine‐1‐phosphate suppresses chondrosarcoma metastasis by upregulation of tissue inhibitor of metalloproteinase 3 through suppressing miR‐101 expression

et al. 2017

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Chondrosarcoma is the second most common primary malignancy form of bone cancer, exhibiting resistance to chemotherapy and radiation therapy as well as developing high metastasis ability in late‐stage tumors. Thus, understanding the metastatic processes of chondrosarcoma is considered a strategy for the treatment of this disease. Sphingosine 1‐phosphate (S1P), a bioactive sphingolipid, is produced intracellularly by sphingosine kinase (SphK) and is regarded as a second signaling molecule that regulates inflammation, proliferation, angiogenesis, and metastasis. However, the effect of S1P on chondrosarcoma remains uncertain. As demonstrated by the transwell, immunoblotting, and real‐time PCR analyses, we found that S1P inhibited cell migration and MMP‐2 expression through the upregulation of the tissue inhibitor of metalloproteinase‐3 (TIMP‐3) expression in human chondrosarcoma cells. Additionally, we also showed that microRNA (miRNA)‐101, which targets the 3′ untranslated region (3′UTR) of TIMP‐3, decreased significantly following S1P treatment. After transfection with miR‐101 mimics, the S1P‐regulated cell migration and TIMP‐3 expression were both reversed. Furthermore, we also showed that the S1P‐inhibited cell migration is mediated through the c‐Src/MEK/ERK signaling axis. Meanwhile, the in vivo study indicated that overexpression of SphK1 decreases chondrosarcoma metastasis to the lungs. Our results illustrate the clinical significance between SphK1, TIMP‐3, and miR‐101 in human chondrosarcoma patients. Taken together, our results suggest that S1P and miR‐101 may prove to be potential therapeutic targets for future chondrosarcoma treatment.

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The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9

Cited by 71 publications

References 53 publications

Exposure to Concentrated Ambient Fine Particulate Matter Induces Vascular Endothelial Dysfunction via miR-21

Exposure to Concentrated Ambient Fine Particulate Matter Induces Vascular Endothelial Dysfunction via miR-21

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

Sphingosine‐1‐phosphate suppresses chondrosarcoma metastasis by upregulation of tissue inhibitor of metalloproteinase 3 through suppressing miR‐101 expression

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