Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer
- 1.1k Downloads
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.
KeywordsmiR-494 Angiogenesis Non-small cell lung cancer Microvesicle
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.
- 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.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
- 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
- 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
- 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
- 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
- 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
- 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.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.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.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
- 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