title: Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer.
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.
authors.affiliation: Institute of Cardiovascular Science, Peking University Health Science Center, 38 Xueyuan Rd, Beijing, 100191, China.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Mao
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Xi
authors.initials: X
authors.lastname: Fang
authors.forename: Yahan
authors.initials: Y
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Fang
authors.forename: Lianjun
authors.initials: L
authors.lastname: Lin
authors.forename: Xinmin
authors.initials: X
authors.lastname: Liu
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D014945:Wound Healing
chemical_list: C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C547168:MIRN494 microRNA, human; D035683:MicroRNAs; C550178:Mirn494 microRNA, mouse; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse