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Angiogenesis

, Volume 18, Issue 3, pp 373–382 | Cite as

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

  • Guangmei Mao
  • Yan Liu
  • Xi Fang
  • Yahan Liu
  • Li Fang
  • Lianjun Lin
  • Xinmin Liu
  • Nanping WangEmail author
Original Paper

Abstract

Angiogenesis, a crucial step in tumor growth and metastasis, is regulated by various pro- or anti-angiogenic factors. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, roles of tumor-derived microRNAs in regulating tumor vascularization remain to be elucidated. In this study, we found that delivery of miR-494 into human vascular endothelial cells (ECs) enhanced the EC migration and promoted angiogenesis. The angiogenic effect of miR-494 was mediated by the targeting of PTEN and the subsequent activation of Akt/eNOS pathway. Importantly, co-culture experiments demonstrated that a lung cancer cell line, A549, secreted and delivered miR-494 into ECs via a microvesicle-mediated route. In addition, we found that the expression of miR-494 was induced in the tumor cells in response to hypoxia, likely via a HIF-1α-mediated mechanism. Furthermore, a specific miR-494 antagomiR effectively inhibited angiogenesis and attenuated the growth of tumor xenografts in nude mice. Taken together, these results demonstrated that miR-494 is a novel tumor-derived paracrine signal to promote angiogenesis and tumor growth under hypoxic condition.

Keywords

miR-494 Angiogenesis Non-small cell lung cancer Microvesicle 

Notes

Acknowledgments

This work was supported by grants from the National Science Foundation of China (#30881220108005, 31430045 and 81470373) and the Provincial Office of Science and Technology, Shaanxi (2011KTCQ03-14).

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10456_2015_9474_MOESM1_ESM.pdf (160 kb)
Supplementary material 1 (PDF 160 kb)

References

  1. 1.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136(2):215–233. doi: 10.1016/j.cell.2009.01.002 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Wang Y, Lee CG (2009) MicroRNA and cancer—focus on apoptosis. J Cell Mol Med 13(1):12–23. doi: 10.1111/j.1582-4934.2008.00510.x PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Stenvang J, Petri A, Lindow M, Obad S, Kauppinen S (2012) Inhibition of microRNA function by antimiR oligonucleotides. Silence 3(1):1. doi: 10.1186/1758-907X-3-1 PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Jones K, Nourse JP, Keane C, Bhatnagar A, Gandhi MK (2014) Plasma microRNA are disease response biomarkers in classical Hodgkin lymphoma. Clin Cancer Res 20(1):253–264. doi: 10.1158/1078-0432.CCR-13-1024 PubMedCrossRefGoogle Scholar
  5. 5.
    Ries J, Vairaktaris E, Agaimy A, Kintopp R, Baran C, Neukam FW, Nkenke E (2014) miR-186, miR-3651 and miR-494: potential biomarkers for oral squamous cell carcinoma extracted from whole blood. Oncol Rep 31(3):1429–1436. doi: 10.3892/or.2014.2983 PubMedGoogle Scholar
  6. 6.
    Lim L, Balakrishnan A, Huskey N, Jones KD, Jodari M, Ng R, Song G, Riordan J, Anderton B, Cheung ST, Willenbring H, Dupuy A, Chen X, Brown D, Chang AN, Goga A (2014) MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology 59(1):202–215. doi: 10.1002/hep.26662 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Liu Y, Lai L, Chen Q, Song Y, Xu S, Ma F, Wang X, Wang J, Yu H, Cao X, Wang Q (2012) MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol 188(11):5500–5510. doi: 10.4049/jimmunol.1103505 PubMedCrossRefGoogle Scholar
  8. 8.
    Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17(11):1359–1370. doi: 10.1038/nm.2537 PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang Y, Yang P, Wang XF (2014) Microenvironmental regulation of cancer metastasis by miRNAs. Trends Cell Biol 24(3):153–160. doi: 10.1016/j.tcb.2013.09.007 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Wang X, Fang X, Zhou J, Chen Z, Zhao B, Xiao L, Liu A, Li YS, Shyy JY, Guan Y, Chien S, Wang N (2013) Shear stress activation of nuclear receptor PXR in endothelial detoxification. Proc Natl Acad Sci USA 110(32):13174–13179. doi: 10.1073/pnas.1312065110 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Wang N, Verna L, Hardy S, Zhu Y, Ma KS, Birrer MJ, Stemerman MB (1999) c-Jun triggers apoptosis in human vascular endothelial cells. Circ Res 85(5):387–393PubMedCrossRefGoogle Scholar
  12. 12.
    Leung EL, Fiscus RR, Tung JW, Tin VP, Cheng LC, Sihoe AD, Fink LM, Ma Y, Wong MP (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE 5(11):e14062. doi: 10.1371/journal.pone.0014062 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Szot CS, Buchanan CF, Freeman JW, Rylander MN (2013) In vitro angiogenesis induced by tumor-endothelial cell co-culture in bilayered, collagen I hydrogel bioengineered tumors. Tissue Eng Part C Methods 19(11):864–874. doi: 10.1089/ten.TEC.2012.0684 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Zhu TS, Costello MA, Talsma CE, Flack CG, Crowley JG, Hamm LL, He X, Hervey-Jumper SL, Heth JA, Muraszko KM, DiMeco F, Vescovi AL, Fan X (2011) Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res 71(18):6061–6072. doi: 10.1158/0008-5472.CAN-10-4269 PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Tang Z, Wang Y, Fan Y, Zhu Y, Chien S, Wang N (2008) Suppression of c-Cbl tyrosine phosphorylation inhibits neointimal formation in balloon-injured rat arteries. Circulation 118(7):764–772. doi: 10.1161/CIRCULATIONAHA.107.761932 PubMedCrossRefGoogle Scholar
  16. 16.
    Liu Y, Tian XY, Mao G, Fang X, Fung ML, Shyy JY, Huang Y, Wang N (2012) Peroxisome proliferator-activated receptor-gamma ameliorates pulmonary arterial hypertension by inhibiting 5-hydroxytryptamine 2B receptor. Hypertension 60(6):1471–1478. doi: 10.1161/HYPERTENSIONAHA.112.198887 PubMedCrossRefGoogle Scholar
  17. 17.
    Liu W, Li JJ, Liu M, Zhang H, Wang N (2015) PPAR-gamma promotes endothelial cell migration By inducing the expression of Sema3g. J Cell Biochem 116(4):514–523. doi: 10.1002/jcb.24994 PubMedCrossRefGoogle Scholar
  18. 18.
    Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71(15):5346–5356. doi: 10.1158/0008-5472.CAN-11-0241 PubMedCrossRefGoogle Scholar
  19. 19.
    Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM (1995) Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 55(22):5310–5314PubMedGoogle Scholar
  20. 20.
    Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848. doi: 10.1158/0008-5472.CAN-06-1010 PubMedCrossRefGoogle Scholar
  21. 21.
    Wang X, Zhang X, Ren XP, Chen J, Liu H, Yang J, Medvedovic M, Hu Z, Fan GC (2010) MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury. Circulation 122(13):1308–1318. doi: 10.1161/CIRCULATIONAHA.110.964684 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Al-Nedawi K, Meehan B, Rak J (2009) Microvesicles: messengers and mediators of tumor progression. Cell Cycle 8(13):2014–2018PubMedCrossRefGoogle Scholar
  23. 23.
    Muralidharan-Chari V, Clancy JW, Sedgwick A, D’Souza-Schorey C (2010) Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci 123(Pt 10):1603–1611. doi: 10.1242/jcs.064386 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L (2007) Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67(7):2912–2915. doi: 10.1158/0008-5472.CAN-07-0520 PubMedCrossRefGoogle Scholar
  25. 25.
    D’Souza-Schorey C, Clancy JW (2012) Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev 26(12):1287–1299. doi: 10.1101/gad.192351.112 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Yamada N, Tsujimura N, Kumazaki M, Shinohara H, Taniguchi K, Nakagawa Y, Naoe T, Akao Y (2014) Colorectal cancer cell-derived microvesicles containing microRNA-1246 promote angiogenesis by activating Smad 1/5/8 signaling elicited by PML down-regulation in endothelial cells. Biochim Biophys Acta 1839(11):1256–1272. doi: 10.1016/j.bbagrm.2014.09.002 PubMedCrossRefGoogle Scholar
  27. 27.
    Liu L, Jiang Y, Zhang H, Greenlee AR, Han Z (2010) Overexpressed miR-494 down-regulates PTEN gene expression in cells transformed by anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide. Life Sci 86(5–6):192–198. doi: 10.1016/j.lfs.2009.12.002 PubMedCrossRefGoogle Scholar
  28. 28.
    Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250PubMedCrossRefGoogle Scholar
  29. 29.
    Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26(2):281–290. doi: 10.1007/s10555-007-9066-y PubMedCrossRefGoogle Scholar
  30. 30.
    Voellenkle C, Rooij J, Guffanti A, Brini E, Fasanaro P, Isaia E, Croft L, David M, Capogrossi MC, Moles A, Felsani A, Martelli F (2012) Deep-sequencing of endothelial cells exposed to hypoxia reveals the complexity of known and novel microRNAs. RNA 18(3):472–484. doi: 10.1261/rna.027615.111 PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Cha ST, Chen PS, Johansson G, Chu CY, Wang MY, Jeng YM, Yu SL, Chen JS, Chang KJ, Jee SH, Tan CT, Lin MT, Kuo ML (2010) MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis. Cancer Res 70(7):2675–2685. doi: 10.1158/0008-5472.CAN-09-2448 PubMedCrossRefGoogle Scholar
  32. 32.
    Puissegur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, Maurin T, Lebrigand K, Cardinaud B, Hofman V, Fourre S, Magnone V, Ricci JE, Pouyssegur J, Gounon P, Hofman P, Barbry P, Mari B (2011) miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ 18(3):465–478. doi: 10.1038/cdd.2010.119 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, Chandrashekhar YS, Hall JL, Roy S, Zeng Y, Ramakrishnan S (2010) Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest 120(11):4141–4154. doi: 10.1172/JCI42980 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Chan YC, Khanna S, Roy S, Sen CK (2011) miR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells. J Biol Chem 286(3):2047–2056. doi: 10.1074/jbc.M110.158790 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, Kung HF, Lai L, Jiang BH (2011) MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1alpha expression. PLoS ONE 6(4):e19139. doi: 10.1371/journal.pone.0019139 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Seok JK, Lee SH, Kim MJ, Lee YM (2014) MicroRNA-382 induced by HIF-1alpha is an angiogenic miR targeting the tumor suppressor phosphatase and tensin homolog. Nucleic Acids Res 42(12):8062–8072. doi: 10.1093/nar/gku515 PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Romano G, Acunzo M, Garofalo M, Di Leva G, Cascione L, Zanca C, Bolon B, Condorelli G, Croce CM (2012) MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation. Proc Natl Acad Sci USA 109(41):16570–16575. doi: 10.1073/pnas.1207917109 PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Wang J, Chen H, Liao Y, Chen N, Liu T, Zhang H, Zhang H (2015) Expression and clinical evidence of miR-494 and PTEN in non-small cell lung cancer. Tumor Biol. doi: 10.1007/s13277-015-3416-0 Google Scholar
  39. 39.
    Cui FM, Li JX, Chen Q, Du HB, Zhang SY, Nie JH, Cao JP, Zhou PK, Hei TK, Tong J (2013) Radon-induced alterations in micro-RNA expression profiles in transformed BEAS2B cells. J Toxicol Environ Health A 76(2):107–119. doi: 10.1080/15287394.2013.738176 PubMedCrossRefGoogle Scholar
  40. 40.
    He W, Li Y, Chen X, Lu L, Tang B, Wang Z, Pan Y, Cai S, He Y, Ke Z (2014) miR-494 acts as an anti-oncogene in gastric carcinoma by targeting c-myc. J Gastroenterol Hepatol 29(7):1427–1434. doi: 10.1111/jgh.12558 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Guangmei Mao
    • 1
  • Yan Liu
    • 1
  • Xi Fang
    • 1
  • Yahan Liu
    • 1
  • Li Fang
    • 1
  • Lianjun Lin
    • 2
  • Xinmin Liu
    • 2
  • Nanping Wang
    • 1
    • 3
    Email author
  1. 1.Institute of Cardiovascular SciencePeking University Health Science CenterBeijingChina
  2. 2.Geriatric DepartmentPeking University First HospitalBeijingChina
  3. 3.Cardiovascular Research CenterXi’an Jiaotong UniversityXi’anChina

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