Abstract
Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been identified as a regulatory molecule in angiogenesis. The goal of this study was to illustrate how MEG3 affects the angiogenesis of vascular endothelial cells. Expression of MEG3, miR-147 and intracellular cell adhesion molecule-1 (ICAM-1) in human microvascular endothelial cell line (HMEC-1) was altered by transfection, then cell viability, apoptosis, migration, tube formation, as well as the correlation among MEG3, miR-147 and ICAM-1 were explored. MEG3 was down-regulated during tube formation of HMEC-1 cells. MEG3 expression suppressed cells viability, migration and tube formation, while it induced apoptosis. MEG3 could bind with miR-147 and repress miR-147 expression. MiR-147 induced ICAM-1 expression, and contained ICAM-1 target sequences. The anti-atherogenic actions of MEG3 were inhibited by miR-147, and the anti-atherogenic actions of miR-147 suppression were also inhibited when ICAM-1 was overexpressed. Further, ICAM-1 overexpression showed activated roles in Wnt/β-catenin and Jak/Stat signaling pathways. In low-density lipoprotein receptor (Ldlr)−/− mice, MEG3 overexpression reduced CD68+, CD3+ and ICAM-1 areas in lesions and increased collagen content. MEG3 inhibited HMEC-1 cell growth, migration and tube formation. The anti-atherogenic actions of MEG3 might be mediated via sponging miR-147, and thereby repressing the expression of ICAM-1.
Conflict of interest statement: The authors declare that they have no conflict of interest regarding this study.
References
Balik, V., Srovnal, J., Sulla, I., Kalita, O., Foltanova, T., Vaverka, M., Hrabalek, L., and Hajduch, M. (2013). MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas. J. Neurooncol. 112, 1–8.10.1007/s11060-012-1038-6Search in Google Scholar
Binse, I., Ueberberg, B., Sandalcioglu, I.E., Flitsch, J., Luedecke, D.K., Mann, K., and Petersenn, S. (2014). Expression analysis of GADD45gamma, MEG3, and p8 in pituitary adenomas. Horm. Metab. Res. 46, 644–650.10.1055/s-0034-1383566Search in Google Scholar
Braun, M., Pietsch, P., Schror, K., Baumann, G., and Felix, S.B. (1999). Cellular adhesion molecules on vascular smooth muscle cells. Cardiovasc. Res. 41, 395–401.10.1016/S0008-6363(98)00302-2Search in Google Scholar
Cao, M.X., Jiang, Y.P., Tang, Y.L., and Liang, X.H. (2017). The crosstalk between lncRNA and microRNA in cancer metastasis: orchestrating the epithelial-mesenchymal plasticity. Oncotarget 8, 12472–12483.10.18632/oncotarget.13957Search in Google Scholar PubMed PubMed Central
Chunharojrith, P., Nakayama, Y., Jiang, X., Kery, R.E., Ma, J., De La Hoz Ulloa, C.S., Zhang, X., Zhou, Y., and Klibanski, A. (2015). Tumor suppression by MEG3 lncRNA in a human pituitary tumor derived cell line. Mol. Cell. Endocrinol. 416, 27–35.10.1016/j.mce.2015.08.018Search in Google Scholar PubMed PubMed Central
Congrains, A., Kamide, K., Oguro, R., Yasuda, O., Miyata, K., Yamamoto, E., Kawai, T., Kusunoki, H., Yamamoto, H., Takeya, Y., et al. (2012). Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis 220, 449–455.10.1016/j.atherosclerosis.2011.11.017Search in Google Scholar PubMed
Duzagac, F., Inan, S., Ela Simsek, F., Acikgoz, E., Guven, U., Khan, S.A., Rouhrazi, H., Oltulu, F., Aktug, H., Erol, A., et al. (2015). JAK/STAT pathway interacts with intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) while prostate cancer stem cells form tumor spheroids. J. Buon. 20, 1250–1257.Search in Google Scholar
Fabian, M.R., Sonenberg, N., and Filipowicz, W. (2010). Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379.10.1146/annurev-biochem-060308-103103Search in Google Scholar PubMed
Ferrara, N. (2009). Vascular endothelial growth factor. Arterioscler Thromb. Vasc. Biol. 29, 789–791.10.1161/ATVBAHA.108.179663Search in Google Scholar PubMed
Greife, A., Knievel, J., Ribarska, T., Niegisch, G., and Schulz, W.A. (2014). Concomitant downregulation of the imprinted genes DLK1 and MEG3 at 14q32.2 by epigenetic mechanisms in urothelial carcinoma. Clin. Epigenetics 6, 29.10.1186/1868-7083-6-29Search in Google Scholar PubMed PubMed Central
Grote, K., Luchtefeld, M., and Schieffer, B. (2005). JANUS under stress–role of JAK/STAT signaling pathway in vascular diseases. Vascul. Pharmacol. 43, 357–363.10.1016/j.vph.2005.08.021Search in Google Scholar PubMed
Han, L., Dong, Z., Liu, N., Xie, F., and Wang, N. (2017). Maternally expressed gene 3 (MEG3) enhances PC12 cell hypoxia injury by targeting MiR-147. Cell. Physiol. Biochem. 43, 2457–2469.10.1159/000484452Search in Google Scholar
He, Y., Luo, Y., Liang, B., Ye, L., Lu, G., and He, W. (2017a). Potential applications of MEG3 in cancer diagnosis and prognosis. Oncotarget 8, 73282–73295.10.18632/oncotarget.19931Search in Google Scholar
He, C., Yang, W., Yang, J., Ding, J., Li, S., Wu, H., Zhou, F., Jiang, Y., Teng, L., and Yang, J. (2017b). Long noncoding RNA MEG3 negatively regulates proliferation and angiogenesis in vascular endothelial cells. DNA Cell Biol. 36, 475–481.10.1089/dna.2017.3682Search in Google Scholar
Holdt, L.M., Beutner, F., Scholz, M., Gielen, S., Gabel, G., Bergert, H., Schuler, G., Thiery, J., and Teupser, D. (2010). ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler. Thromb. Vasc. Biol. 30, 620–627.10.1161/ATVBAHA.109.196832Search in Google Scholar
Jalali, S., Bhartiya, D., Lalwani, M.K., Sivasubbu, S., and Scaria, V. (2013). Systematic transcriptome wide analysis of lncRNA-miRNA interactions. PLoS One 8, e53823.10.1371/journal.pone.0053823Search in Google Scholar
Janowski, B.A., Younger, S.T., Hardy, D.B., Ram, R., Huffman, K.E., and Corey, D.R. (2007). Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat. Chem. Biol. 3, 166–173.10.1038/nchembio860Search in Google Scholar
Li, Z.Y., Yang, L., Liu, X.J., Wang, X.Z., Pan, Y.X., and Luo, J.M. (2018a). Corrigendum to “the long noncoding RNA MEG3 and its target miR-147 regulate JAK/STAT pathway in advanced chronic myeloid leukemia” [EBioMedicine 35 (2018) 61–75]. EBioMedicine 37, 569.10.1016/j.ebiom.2018.10.049Search in Google Scholar
Li, Z.Y., Yang, L., Liu, X.J., Wang, X.Z., Pan, Y.X., and Luo, J.M. (2018b). The long noncoding RNA MEG3 and its target miR-147 regulate JAK/STAT pathway in advanced chronic myeloid leukemia. EBioMedicine 34, 61–75.10.1016/j.ebiom.2018.07.013Search in Google Scholar
Liu, Y., Zheng, L., Wang, Q., and Hu, Y.W. (2017). Emerging roles and mechanisms of long noncoding RNAs in atherosclerosis. Int. J. Cardiol. 228, 570–582.10.1016/j.ijcard.2016.11.182Search in Google Scholar
Lopez, A.D., Mathers, C.D., Ezzati, M., Jamison, D.T., and Murray, C.J. (2006). Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367, 1747–1757.10.1016/S0140-6736(06)68770-9Search in Google Scholar
Mattick, J.S. and Makunin, I.V. (2006). Non-coding RNA. Hum. Mol. Genet. 15 (Spec No 1), R17–R29.10.1093/hmg/ddl046Search in Google Scholar PubMed
Mendes, D.S., Dantas, M.L., Gomes, J.M., Santos, W.L., Silva, A.Q., Guimaraes, L.H., Machado, P.R., Carvalho, E.M., and Arruda, S. (2013). Inflammation in disseminated lesions: an analysis of CD4+, CD20+, CD68+, CD31+ and vW+ cells in non-ulcerated lesions of disseminated leishmaniasis. Mem. Inst. Oswaldo Cruz. 108, 18–22.10.1590/S0074-02762013000100003Search in Google Scholar PubMed PubMed Central
Miyoshi, N., Wagatsuma, H., Wakana, S., Shiroishi, T., Nomura, M., Aisaka, K., Kohda, T., Surani, M.A., Kaneko-Ishino, T., and Ishino, F. (2000). Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q. Genes Cells 5, 211–220.10.1046/j.1365-2443.2000.00320.xSearch in Google Scholar PubMed
Ortiz-Munoz, G., Martin-Ventura, J.L., Hernandez-Vargas, P., Mallavia, B., Lopez-Parra, V., Lopez-Franco, O., Munoz-Garcia, B., Fernandez-Vizarra, P., Ortega, L., Egido, J., et al. (2009). Suppressors of cytokine signaling modulate JAK/STAT-mediated cell responses during atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 525–531.10.1161/ATVBAHA.108.173781Search in Google Scholar PubMed
Pan, J.X. (2017). LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-κB signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 21, 322–328.Search in Google Scholar
Parma, L., Baganha, F., Quax, P.H.A., and de Vries, M.R. (2017). Plaque angiogenesis and intraplaque hemorrhage in atherosclerosis. Eur. J. Pharmacol. 816, 107–115.10.1016/j.ejphar.2017.04.028Search in Google Scholar PubMed
Place, R.F., Li, L.C., Pookot, D., Noonan, E.J., and Dahiya, R. (2008). MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc. Natl. Acad. Sci. USA 105, 1608–1613.10.1073/pnas.0707594105Search in Google Scholar PubMed PubMed Central
Qiu, G.Z., Tian, W., Fu, H.T., Li, C.P., and Liu, B. (2016). Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem. Biophys. Res. Commun. 471, 135–141.10.1016/j.bbrc.2016.01.164Search in Google Scholar PubMed
Rane, S.G. and Reddy, E.P. (2002). JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21, 3334–3358.10.1038/sj.onc.1205398Search in Google Scholar PubMed
Reis, M. and Liebner, S. (2013). Wnt signaling in the vasculature. Exp. Cell Res. 319, 1317–1323.10.1016/j.yexcr.2012.12.023Search in Google Scholar PubMed
Shibuya, M. and Claesson-Welsh, L. (2006). Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res. 312, 549–560.10.1016/j.yexcr.2005.11.012Search in Google Scholar PubMed
Su, W., Xie, W., Shang, Q., and Su, B. (2015). The long noncoding RNA MEG3 is downregulated and inversely associated with VEGF levels in osteoarthritis. Biomed. Res. Int. 2015, 356893.10.1155/2015/356893Search in Google Scholar PubMed PubMed Central
Vallee, A., Vallee, J.N., and Lecarpentier, Y. (2019). Metabolic reprogramming in atherosclerosis: opposed interplay between the canonical WNT/β-catenin pathway and PPARgamma. J. Mol. Cell. Cardiol. 133, 36–46.10.1016/j.yjmcc.2019.05.024Search in Google Scholar PubMed
Wang, X., Wang, Z., Wang, J., Wang, Y., Liu, L., and Xu, X. (2017). LncRNA MEG3 has anti-activity effects of cervical cancer. Biomed. Pharmacother. 94, 636–643.10.1016/j.biopha.2017.07.056Search in Google Scholar PubMed
Weber, C. and Noels, H. (2011). Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422.10.1038/nm.2538Search in Google Scholar PubMed
Wong, D.W.L., Yiu, W.H., Chan, K.W., Li, Y., Li, B., Lok, S.W.Y., Taketo, M.M., Igarashi, P., Chan, L.Y.Y., Leung, J.C.K., et al. (2018). Activated renal tubular Wnt/β-catenin signaling triggers renal inflammation during overload proteinuria. Kidney Int. 93, 1367–1383.10.1016/j.kint.2017.12.017Search in Google Scholar PubMed PubMed Central
Wright, M., Aikawa, M., Szeto, W., and Papkoff, J. (1999). Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells. Biochem. Biophys. Res. Commun. 263, 384–388.10.1006/bbrc.1999.1344Search in Google Scholar PubMed
Wu, Z., He, Y., Li, D., Fang, X., Shang, T., Zhang, H., and Zheng, X. (2017). Long noncoding RNA MEG3 suppressed endothelial cell proliferation and migration through regulating miR-21. Am. J. Transl. Res. 9, 3326–3335.Search in Google Scholar
Zhang, Y., Liu, X., Bai, X., Lin, Y., Li, Z., Fu, J., Li, M., Zhao, T., Yang, H., Xu, R., et al. (2017a). Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR-223/NLRP3 axis. J. Pineal Res. 64, e12449.10.1111/jpi.12449Search in Google Scholar PubMed
Zhang, J., Yao, T., Lin, Z., and Gao, Y. (2017b). Aberrant methylation of MEG3 functions as a potential plasma-based biomarker for cervical cancer. Sci. Rep. 7, 6271.10.1038/s41598-017-06502-7Search in Google Scholar PubMed PubMed Central
Zhou, Y., Zhang, X., and Klibanski, A. (2012). MEG3 noncoding RNA: a tumor suppressor. J. Mol. Endocrinol. 48, R45–R53.10.1530/JME-12-0008Search in Google Scholar PubMed PubMed Central
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