title: microRNA-128 plays a critical role in human non-small cell lung cancer tumourigenesis, angiogenesis and lymphangiogenesis by directly targeting vascular endothelial growth factor-C.
abstract: Recent studies have indicated that microRNAs (miRNAs) are important gene regulators that play critical roles in biological processes and function as either tumour suppressors or oncogenes. Therefore, the expression levels of miRNAs can be important and reliable biomarkers for cancer detection and prognostic prediction, and potentially serve as targets for cancer therapy. In this study, we showed that the expression level of miR-128 was significantly downregulated in non-small cell lung cancer (NSCLC) tissues and cancer cells, and was significantly correlated with NSCLC differentiation, pathological stage and lymph node metastasis. Ectopic miR-128 overexpression significantly suppressed in vitro proliferation, colony formation, immigration and invasion, and induced G1 arrest and apoptosis of NSCLC cells. Interestingly, ectopic miR-128 overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-C expression and reduce the activity of a luciferase reporter containing the VEGF-C 3'-untranslated region. In addition, overexpression of miR-128 in NSCLC cells and human umbilical vein endothelial cells (HUVECs) cells led to decreased expression of VEGF-A, vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3, critical factors responsible for cancer angiogenesis and lymphangiogenesis, and subsequently decreased phosphorylation of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (AKT) and p38 signalling pathways. Furthermore, in vivo restoration of miR-128 significantly suppressed tumourigenicity of A549 cells in nude mice and inhibited both angiogenesis and lymphangiogenesis of tumour xenografts. These findings suggest that miR-128 could play a role in NSCLC tumourigenesis at least in part by modulation of angiogenesis and lymphangiogenesis through targeting VEGF-C, and could simultaneously block ERK, AKT and p38 signalling pathways. Therapeutic strategies to restore miR-128 in NSCLC could be useful to inhibit tumour progression.
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China; School of Basic Medical Science, Harbin Medical University, Harbin 150086, China; Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China; School of Basic Medical Science, Harbin Medical University, Harbin 150086, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China.
authors.forename: Yuezhen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China.
authors.forename: Zaishun
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China.
authors.forename: Guibo
authors.initials: G
authors.lastname: Liu
authors.affiliation: School of Basic Medical Science, Harbin Medical University, Harbin 150086, China.
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.affiliation: School of Basic Medical Science, Harbin Medical University, Harbin 150086, China.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China.
authors.forename: Kejian
authors.initials: K
authors.lastname: Feng
authors.affiliation: Key Laboratory of Tumor Prevention and Treatment (Heilongjiang Higher Education Institutions), Mudanjiang Medical University, Mudanjiang 157011, China; School of Basic Medical Science, Harbin Medical University, Harbin 150086, China; Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA. Electronic address: fengyukuan@163.com.
authors.forename: Yukuan
authors.initials: Y
authors.lastname: Feng
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042583:Lymphangiogenesis / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C
keywords: Non-small cell lung cancer; VEGF-C; miRNA-128; microRNA