Effect of silencing lncRNATUG1 on rapamycin‑induced inhibition of endothelial cell proliferation and migration

Gao,Xue; Zhang,Tao; Zeng,Xi‑Yun; Li,Guo‑Jian; Du,Ling‑Juan; Ma,Zhen‑Huan; Wan,Jia; Yang,Yong

doi:10.3892/etm.2018.6352

Effect of silencing lncRNATUG1 on rapamycin‑induced inhibition of endothelial cell proliferation and migration

Authors:
- Xue Gao
- Tao Zhang
- Xi‑Yun Zeng
- Guo‑Jian Li
- Ling‑Juan Du
- Zhen‑Huan Ma
- Jia Wan
- Yong Yang
View Affiliations

Affiliations: Department of Geriatric Disease, The First Hospital of Kunming, Kunming, Yunnan 650011, P.R. China, Department of Vascular Surgery, The Fourth Affiliated Hospital, Kunming Medical University, The Second People's Hospital of Yunnan Province, Kunming, Yunnan 650021, P.R. China
Published online on: June 26, 2018 https://doi.org/10.3892/etm.2018.6352
Pages: 1891-1899
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Angiogenesis refers to the formation of new blood vessels from existing blood vessels. The proliferation and migration of endothelial cells serves a key function in this process. Previous research has demonstrated that rapamycin suppresses endothelial cell proliferation and migration, as well as angiogenesis. However, the mechanism by which rapamycin inhibits the proliferation and migration of endothelial cells remains unclear. Long noncoding RNAs (lncRNAs) serve a key function in the regulation of endothelial cell function. The aim of the current study was to investigate whether lncRNA taurine upregulated 1 (lncRNATUG1) is involved in rapamycin‑induced inhibition of proliferation and migration in human umbilical vein endothelial cells (HUVECs). Reverse transcription quantitative polymerase chain reaction results indicated that the expression of lncRNATUG1 was upregulated in HUVECs that had been cultured with rapamycin. Subsequently, HUVECs were transfected with siRNAs and CCK‑8 assays were performed to detect cell proliferation; additionally, flow cytometry was employed to detect cell apoptosis, and wound healing assays were performed to investigate cell migration. The results demonstrated that rapamycin suppressed the proliferation and migration of HUVECs, and promoted the apoptosis of HUVECs. In addition, rapamycin downregulated the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)‑2 and MMP‑9 in HUVECs. However, silencing of lncRNATUG1 was revealed to attenuate rapamycin‑induced inhibition of cellular proliferation and migration of HUVECs, as well as upregulating the expression of VEGF, MMP2 and MMP‑9. These results suggested that lncRNATUG1 regulates rapamycin‑induced inhibition of endothelial cell proliferation and migration. Therefore, lncRNATUG1 may serve a key function in rapamycin‑induced inhibition of endothelial cell proliferation and migration.

View Figures

View References

1	Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009. View Article : Google Scholar : PubMed/NCBI
2	Qureshi 1A, Mattick JS and Mehler MF: Long non-coding RNAs in nervous system function and disease. Brain Res. 1338:20–35. 2010. View Article : Google Scholar : PubMed/NCBI
3	Wapinski O and Chang HY: Long noncoding RNAs and human disease. Trends Cell Biol. 21:354–361. 2011. View Article : Google Scholar : PubMed/NCBI
4	Dinger ME, Amaral PP, Mercer TR, Pang KC, Bruce SJ, Gardiner BB, Askarian-Amiri ME, Ru K, Soldà G, Simons C, et al: Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 18:1433–1445. 2008. View Article : Google Scholar : PubMed/NCBI
5	Kanduri C: Long noncoding RNA and epigenomics. Adv Exp Med Biol. 722:174–195. 2015. View Article : Google Scholar
6	Yin DD, Zhang E B, You L H, Wang N, Wang LT, Jin FY, Zhu YN, Cao LH, Yuan QX, De W and Tang W: Down-regulation of lncRNA TUG1 affects apoptosis and insulin secretion in mouse pancreatic β cells. Cell Physiol Biochem. 35:1892–1904. 2015. View Article : Google Scholar : PubMed/NCBI
7	Chen J, Jia YS, Liu GZ, Sun Q, Zhang F, Ma S and Wang YJ: Role of LncRNA TUG1 in intervertebral disc degeneration and nucleus pulposus cells via regulating Wnt/β-catenin signaling pathway. BiochemBiophys Res Commun. 491:668–674. 2017. View Article : Google Scholar
8	Michalik KM, You X, Manavski Y, Doddaballapur A, Zörnig M, Braun T, John D, Ponomareva Y, Chen W, Uchida S, et al: Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res. 114:1389–1397. 2014. View Article : Google Scholar : PubMed/NCBI
9	Zhang M, Gu H, Xu W and Zhou X: Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. Int J Cardiol. 203:214–216. 2016. View Article : Google Scholar : PubMed/NCBI
10	Liu JY, Yao J, Li XM, Song YC, Wang XQ, Li YJ, Yan B and Jiang Q: Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus. Cell Death Dis. 5:e15062014. View Article : Google Scholar : PubMed/NCBI
11	Tao H, Cao W, Yang JJ, Shi KH, Zhou X, Liu LP and Li J: Long noncoding RNA H19 controls DUSP5/ERK1/2 axis in cardiac fibroblast proliferation and fibrosis. Cardiovasc Pathol. 25:381–389. 2016. View Article : Google Scholar : PubMed/NCBI
12	Pan JX: LncRNA H19 promotes atherosclerosis by regulating MAPK and NF-kB signaling pathway. Eur Rev Med Pharmacol Sci. 21:322–328. 2017.PubMed/NCBI
13	Ballantyne MD, Pinel K, Dakin R, Vesey AT, Diver L, Mackenzie R, Garcia R, Welsh P, Sattar N, Hamilton G, et al: Smooth Muscle Enriched Long Noncoding RNA (SMILR) Regulates Cell Proliferation. Circulation. 133:2050–2065. 2016. View Article : Google Scholar : PubMed/NCBI
14	Qiu GZ, Tian W, Fu HT, Li CP and Liu B: Long noncoding RNA-MEG3 is involved in diabetes mellitus-related microvascular dysfunction. Biochem Biophys Res Commun. 471:135–141. 2016. View Article : Google Scholar : PubMed/NCBI
15	Young TL, Matsuda T and Cepko CL: The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina. Curr Biol. 15:501–512. 2005. View Article : Google Scholar : PubMed/NCBI
16	Fan S, Yang Z, Ke Z, Huang K, Liu N, Fang X and Wang K: Down-regulation of the long non-coding RNA TUG1 is associated with cell proliferation, migration, and invasion in breast cancer. Biomed Pharmacother. 95:1636–1643. 2017. View Article : Google Scholar : PubMed/NCBI
17	Yun-Bo F, Xiao-Po L, Xiao-Li L, Guo-Long C, Pei Z and Fa-Ming T: LncRNA TUG1 is up-regulated and promotes cell proliferation in osteosarcoma. Open Med (Wars). 11:163–167. 2016.PubMed/NCBI
18	Rosner D, Mccarthy N and Bennett M: Rapamycin inhibits human in stent restenosis vascular smooth muscle cells independently of pRB phosphorylation and p53. Cardiovasc Res. 66:601–610. 2005. View Article : Google Scholar : PubMed/NCBI
19	Kawatsu S, Oda KY, Tabata Y and Tabayashi K: External application of rapamycin-eluting film at anastomotic sites inhibits neointimal hyperplasia in a canine model. Ann Thorac Surg. 84:560–567. 2007. View Article : Google Scholar : PubMed/NCBI
20	van der Heijden DJ, Westendorp IC, Riezebos RK, Kiemeneij F, Slagboom T, van der Wieken LR and Laarman GJ: Lack of efficacy of clopidogrel pre-treatment in the prevention of myocardial damage after elective stent implantation. J Am Coll Cardiol. 44:20–24. 2004. View Article : Google Scholar : PubMed/NCBI
21	Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D and Hod H: Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 109:3171–3175. 2004. View Article : Google Scholar : PubMed/NCBI
22	Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ and Tantry US: Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST study. J Am Coll Cardiol. 46:1827–1832. 2005. View Article : Google Scholar : PubMed/NCBI
23	Geisler T, Langer H, Wydymus M, Göhring K, Zürn C, Bigalke B, Stellos K, May AE and Gawaz M: Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J. 27:2420–2425. 2006. View Article : Google Scholar : PubMed/NCBI
24	Moss SC, Lightell DJ Jr, Marx SO, Marks AR and Woodset TC: Rapamycin Regulates Endothelial Cell Migration through Regulation of the Cyclin-dependent Kinase Inhibitor p27Kip1. J Biol Chem. 285:11991–11997. 2010. View Article : Google Scholar : PubMed/NCBI
25	Li E, Zhao Z, Ma B and Zhang J: Long noncoding RNA HOTAIR promotes the proliferation and metastasis of osteosarcoma cells through the AKT/mTOR signaling pathway. Exp Ther Med. 14:5321–5328. 2017.PubMed/NCBI
26	Wang Y, Wang Y, Li J, Zhang Y, Yin H and Han B: CRNDE, a long-noncoding RNA, promotes glioma cell growth and invasion through mTOR signaling. Cancer Lett. 367:122–128. 2015. View Article : Google Scholar : PubMed/NCBI
27	Matsumoto A, Pasut A, Matsumoto M, Yamashita R, Fung J, Monteleone E, Saghatelian A, Nakayama KI, Clohessy JG and Pandolfi PP: mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature. 541:228–232. 2017. View Article : Google Scholar : PubMed/NCBI
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
29	Muñoz-Chápuli R, Quesada AR and Medina Angel M: Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci. 61:2224–2243. 2004. View Article : Google Scholar : PubMed/NCBI
30	Lamalice L, Le Boeuf F and Huot J: Endothelial cell migration during angiogenesis. Circ Res. 100:782–794. 2007. View Article : Google Scholar : PubMed/NCBI
31	Wu G, Cai J, Han Y, Chen J, Huang ZP, Chen C, Cai Y, Huang H, Yang Y, Liu Y, et al: LincRNA-p21 Regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis and atherosclerosis by enhancing p53 activity. Circulation. 130:1452–1465. 2014. View Article : Google Scholar : PubMed/NCBI
32	Yan B, Yao J, Liu J Y, Li XM, Wang XQ, Li YJ, Tao ZF, Song YC, Chen Q and Jiang Q: lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res. 116:1143–1156. 2015. View Article : Google Scholar : PubMed/NCBI
33	Zhang Y, Ma G, Li C, Cao Z, Qie F and Xu X: Baicaleininhibits VSMCs proliferation via regulating LncRNAAK021954 gene expression. Int J Clin Exp Med. 8:22129–22138. 2015.PubMed/NCBI
34	Li J, Zhang M, An G and Ma Q: LncRNA TUG1 acts as a tumor suppressor in human glioma by promoting cell apoptosis. Exp Biol Med (Maywood). 241:644–649. 2016. View Article : Google Scholar : PubMed/NCBI
35	Hu Y, Sun X, Mao C, Guo G, Ye S, Xu J, Zou R, Chen J, Wang L, Duan P and Xue X: Upregulation of long noncoding RNA TUG1 promotes cervical cancer cell proliferation and migration. Cancer Med. 6:471–482. 2017. View Article : Google Scholar : PubMed/NCBI
36	Zhao Z, Wang B, Hao J, Man W, Chang Y, Ma S, Hu Y, Liu F and Yang J: Downregulation of the long non-coding RNA taurine-upregulated gene 1 inhibits glioma cell proliferation and invasion and promotes apoptosis. Oncol Lett. 15:4026–4032. 2018.PubMed/NCBI
37	Zhang M, Lu W, Huang YQ, Shi JZ, Wu X, Zhang XL, Jiang RZ, Cai ZM and Wu S: Downregulation of the long noncoding RNA TUG1 inhibits the proliferation, migration, invasion and promotes apoptosis of renal cell carcinoma. J Mol Histol. 47:421–428. 2016. View Article : Google Scholar : PubMed/NCBI
38	Han YH, Liu YC, Gui YT and Cai ZM: Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. J Surg Oncol. 107:555–559. 2013. View Article : Google Scholar : PubMed/NCBI
39	Cai H, Xue Y, Wang P, Wang Z, Li Z, Hu Y, Li Z, Shang X and Liu Y: The long noncoding RNA TUG1 regulates blood-tumor barrier permeability by targeting miR-144. Oncotarget. 6:19759–19779. 2015. View Article : Google Scholar : PubMed/NCBI
40	Chen C, Cheng GQ, Yang XN, Li CS, Shi R and Zhao NN: Tanshinol suppresses endothelial cells apoptosis in mice with atherosclerosis via lncRNA TUG1 up-regulating the expression of miR-26a. Am J Transl Res. 8:2981–2991. 2016.PubMed/NCBI
41	Liu HT, Li F, Wang WY, Li XJ, Liu YM, Wang RA, Guo WY and Wang HC: Rapamycin inhibits re-endothelialization after percutaneous coronary intervention by impeding the proliferation and migration of endothelial cells and inducing apoptosis of endothelial progenitor cells. Tex Heart Inst J. 37:194–201. 2010.PubMed/NCBI
42	Wang Y, Chen J, Tang W, Zhang Y and Li X: Rapamycin inhibits the proliferation of endothelial cells in hemangioma by blocking the mTOR-FABP4 pathway. Biomed Pharmacother. 85:272–279. 2017. View Article : Google Scholar : PubMed/NCBI
43	Medici D and Olsen BR: Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF. PloS One. 7:e429132012. View Article : Google Scholar : PubMed/NCBI
44	Xue D, Zhou C, Lu H, Xu R, Xu X and He X: LncRNA GAS5 inhibits proliferation and progression of prostate cancer by targeting miR-103 through AKT/mTOR signaling pathway. Tumor Biol. 37:1–11. 2016. View Article : Google Scholar
45	Malakar P, Shilo A, Mogilevsky A, Stein I, Pikarsky E, Nevo Y, Benyamini H, Elgavish S, Zong X, Prasanth KV and Karni R: Long Noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 up-regulation and mTOR activation. Cancer Res. 77:1155–1167. 2017. View Article : Google Scholar : PubMed/NCBI
46	Shui X, Zhou C, Lin W, Yu Y, Feng Y and Kong J: Long non-coding RNA BCAR4 promotes chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway. Exp Biol Med (Maywood). 242:1044–1050. 2017. View Article : Google Scholar : PubMed/NCBI