miR‑141 inhibits glioma vasculogenic mimicry by controlling EphA2 expression

Li,Guoxiong; Huang,Min; Cai,Yingqian; Ke,Yiquan; Yang,Yuantao; Sun,Xinlin

doi:10.3892/mmr.2018.9108

miR‑141 inhibits glioma vasculogenic mimicry by controlling EphA2 expression

Authors:
- Guoxiong Li
- Min Huang
- Yingqian Cai
- Yiquan Ke
- Yuantao Yang
- Xinlin Sun
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Affiliations: Department of Neurosurgery, People's Hospital of Shiyan, Shenzhen, Guangdong 518108, P.R. China, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, Guangdong 510280, P.R. China
Published online on: May 31, 2018 https://doi.org/10.3892/mmr.2018.9108
Pages: 1395-1404
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Human glioma is a pernicious tumor from the central nervous system; it has been reported that microRNAs (miRs) may have carcinogenic or tumor suppressor effects on human glioma. The aim of the present study was to assess miR‑141 expression and functional role in human primary glioma, as well as in tumor‑derived cell lines. The expression of miR‑141 in primary human glioma tissues and cell lines was assessed by employing reverse transcription‑quantitative polymerase chain reaction. Next, its role in cellular growth, migration, invasion and vasculogenic mimicry (VM) regulation was determined using various in vitro and in vivo assays, and on the identification its target gene(s) using luciferase assays. The results demonstrated that miR‑141 expression was downregulated, and Ephrin type‑A receptor 2 (EphA2) was upregulated in the primary human gliomas and human glioma‑derived cell lines tested. In addition, a negative correlation existed between miR‑141 and EphA2 expression levels in glioma grades II, III and IV. Furthermore, exogenous miR‑141 expression resulted in decreased proliferation, migration and invasion, as well as in apoptosis and cell cycle arrest in vitro. It was also revealed that exogenous miR‑141 expression resulted in in vivo inhibition of tumor growth and inhibition of the development of VM. Finally, the present study successfully confirmed that EphA2 was a direct target of miR‑141 in glioma‑derived cells using luciferase assays. Based on these results, it was concluded that miR‑141 may regulate cell proliferation, migration, invasion and VM formation by controlling EphA2 expression; also, its target EphA2 may be a novel diagnostic/prognostic biomarker and a potential anti‑VM therapeutic target.

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1	Demuth T and Berens ME: Molecular mechanisms of glioma cell migration and invasion. J Neurooncol. 70:217–228. 2004. View Article : Google Scholar : PubMed/NCBI
2	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
3	Wu N, Zhao XZ, Liu M, Liu H, Yao W, Zhang Y, Cao S and Lin X: Role of microRNA-26b in glioma development and its mediated regulation on EphA2. PLoS One. 6:e162642011. View Article : Google Scholar : PubMed/NCBI
4	Tanase C, Albulescu R, Codrici E, Popescu ID, Mihai S, Enciu AM, Cruceru ML, Popa AC, Neagu AI, Necula LG, et al: Circulating biomarker panels for targeted therapy in brain tumors. Future Oncol. 11:511–524. 2015. View Article : Google Scholar : PubMed/NCBI
5	Cruceru ML, Enciu AM, Popa AC, Albulescu R, Neagu M, Tanase CP and Constantinescu SN: Signal transduction molecule patterns indicating potential glioblastoma therapy approaches. Onco Targets Ther. 6:1737–1749. 2013.PubMed/NCBI
6	Song Y, Mu L, Han X, Li Q, Dong B, Li H and Liu X: MicroRNA-9 inhibits vasculogenic mimicry of glioma cell lines by suppressing Stathmin expression. J Neurooncol. 115:381–390. 2013. View Article : Google Scholar : PubMed/NCBI
7	Huang M, Ke Y, Sun X, Yu L, Yang Z, Zhang Y, Du M, Wang J, Liu X and Huang S: Mammalian target of rapamycin signaling is involved in the vasculogenic mimicry of glioma via hypoxia-inducible factor-1α. Oncol Rep. 32:1973–1980. 2014. View Article : Google Scholar : PubMed/NCBI
8	Mosch B, Pietzsch D and Pietzsch J: Irradiation affects cellular properties and Eph receptor expression in human melanoma cells. Cell Adh Migr. 6:113–125. 2012. View Article : Google Scholar : PubMed/NCBI
9	Lytle JR, Yario TA and Steitz JA: Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci USA. 104:9667–9672. 2007. View Article : Google Scholar : PubMed/NCBI
10	Bouyssou JM, Manier S, Huynh D, Issa S, Roccaro AM and Ghobrial IM: Regulation of microRNAs in cancer metastasis. Biochim Biophys Acta. 1845:255–265. 2014.PubMed/NCBI
11	Bandres E, Agirre X, Bitarte N, Ramirez N, Zarate R, Roman-Gomez J, Prosper F and Garcia-Foncillas J: Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer. 125:2737–2743. 2009. View Article : Google Scholar : PubMed/NCBI
12	Chen X, Wang X, Ruan A, Han W, Zhao Y, Lu X, Xiao P, Shi H, Wang R, Chen L, et al: miR-141 is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression. Clin Cancer Res. 20:2617–2630. 2014. View Article : Google Scholar : PubMed/NCBI
13	Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn M, Liu H, Panula SP, Chiao E, et al: Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 138:592–603. 2009. View Article : Google Scholar : PubMed/NCBI
14	Mateescu B, Batista L, Cardon M, Gruosso T, de Feraudy Y, Mariani O, Nicolas A, Meyniel JP, Cottu P, Sastre-Garau X and Mechta-Grigoriou F: miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nat Med. 17:1627–1635. 2011. View Article : Google Scholar : PubMed/NCBI
15	Schickel R, Park SM, Murmann AE and Peter ME: miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell. 38:908–915. 2010. View Article : Google Scholar : PubMed/NCBI
16	Hatano M, Eguchi J, Tatsumi T, Kuwashima N, Dusak JE, Kinch MS, Pollack IF, Hamilton RL, Storkus WJ and Okada H: EphA2 as a glioma-associated antigen: A novel target for glioma vaccines. Neoplasi. 7:717–722. 2005. View Article : Google Scholar
17	Yang L, Zhao J, Zhou G, Wang Y, Li L, Yuan H, Nan X, Guan L and Pei X: The 9L(LUC)/Wistar rat glioma model is not suitable for immunotherapy. Neural Regen Res. 7:1406–1411. 2012.PubMed/NCBI
18	Li XY, Zhao Y, Sun MG, Shi JF, Ju RJ, Zhang CX, Li XT, Zhao WY, Mu LM, Zeng F, et al: Multifunctional liposomes loaded with paclitaxel and artemether for treatment of invasive brain glioma. Biomaterials. 35:5591–5604. 2014. View Article : Google Scholar : PubMed/NCBI
19	Xiao F, Zuo Z, Cai G, Kang S, Gao X and Li T: miRecords: An integrated resource for microRNA-target interactions. Nucleic Acids Res. 37:(Database Issue). D105–D110. 2009. View Article : Google Scholar : PubMed/NCBI
20	Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL and Pasquale EB: The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene. 19:6043–6052. 2000. View Article : Google Scholar : PubMed/NCBI
21	Jin Q, Li X and Cao P: EphA2 modulates radiosensitive of hepatocellular carcinoma cells via p38/mitogen-activated protein kinase-mediated signal pathways. Kaohsiung J Med Sci. 31:510–517. 2015. View Article : Google Scholar : PubMed/NCBI
22	Zelinski DP, Zantek ND, Stewart JC, Irizarry AR and Kinch MS: EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 61:2301–2306. 2001.PubMed/NCBI
23	Shao Z, Zhang WF, Chen XM and Shang ZJ: Expression of EphA2 and VEGF in squamous cell carcinoma of the tongue: Correlation with the angiogenesis and clinical outcome. Oral Oncol. 44:1110–1117. 2008. View Article : Google Scholar : PubMed/NCBI
24	Brantley-Sieders DM, Fang WB, Hicks DJ, Zhuang G, Shyr Y and Chen J: Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J. 19:1884–1886. 2005. View Article : Google Scholar : PubMed/NCBI
25	Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al: MicroRNA expression profiles classify human cancers. Nat. 435:834–838. 2005. View Article : Google Scholar
26	Chen B, Huang T, Jiang J, Lv L, Li H and Xia S: miR-141 suppresses proliferation and motility of gastric cancer cells by targeting HDGF. Mol Cell Biochem. 388:211–218. 2014. View Article : Google Scholar : PubMed/NCBI
27	Zhou X, Xia Y, Su J and Zhang G: Down-regulation of miR-141 induced by helicobacter pylori promotes the invasion of gastric cancer by targeting STAT4. Cell Physiol Biochem. 33:1003–1012. 2014. View Article : Google Scholar : PubMed/NCBI
28	Xu L, Li Q, Xu D, Wang Q, An Y, Du Q, Zhang J, Zhu Y and Miao Y: hsa-miR-141 downregulates TM4SF1 to inhibit pancreatic cancer cell invasion and migration. Int J Oncol. 44:459–466. 2014. View Article : Google Scholar : PubMed/NCBI
29	Neves R, Scheel C, Weinhold S, Honisch E, Iwaniuk KM, Trompeter HI, Niederacher D, Wernet P, Santourlidis S and Uhrberg M: Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells. BMC Res Notes. 3:2192010. View Article : Google Scholar : PubMed/NCBI
30	Liu Y, Ding Y, Huang J, Wang S, Ni W, Guan J, Li Q, Zhang Y, Ding Y, Chen B and Chen L: MiR-141 suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS One. 9:e883932014. View Article : Google Scholar : PubMed/NCBI
31	Peng T, Zhang S, Li W, Fu S, Luan Y and Zuo L: MicroRNA-141 inhibits glioma cells growth and metastasis by targeting TGF-β2. Am J Transl Res. 8:3513–3521. 2016.PubMed/NCBI
32	Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, et al: MicroRNA signatures in human ovarian cancer. Cancer Res. 67:8699–8707. 2007. View Article : Google Scholar : PubMed/NCBI
33	Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, et al: MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 299:425–436. 2008. View Article : Google Scholar : PubMed/NCBI
34	El Hallani S, Boisselier B, Peglion F, Rousseau A, Colin C, Idbaih A, Marie Y, Mokhtari K, Thomas JL, Eichmann A, et al: A new alternative mechanism in glioblastoma vascularization: Tubular vasculogenic mimicry. Brain. 133:973–982. 2010. View Article : Google Scholar : PubMed/NCBI
35	Liu XM, Zhang QP, Mu YG, Zhang XH, Sai K, Pang JC, Ng HK and Chen ZP: Clinical significance of vasculogenic mimicry in human gliomas. J Neurooncol. 105:173–179. 2011. View Article : Google Scholar : PubMed/NCBI
36	Folberg R, Hendrix MJ and Maniotis AJ: Vasculogenic mimicry and tumor angiogenesis. Am J Pathol. 156:361–381. 2000. View Article : Google Scholar : PubMed/NCBI