title: The long noncoding RNA MALAT1 promotes tumor-driven angiogenesis by up-regulating pro-angiogenic gene expression.
abstract: Neuroblastoma is the most common solid tumor during early childhood. One of the key features of neuroblastoma is extensive tumor-driven angiogenesis due to hypoxia. However, the mechanism through which neuroblastoma cells drive angiogenesis is poorly understood. Here we show that the long noncoding RNA MALAT1 was upregulated in human neuroblastoma cell lines under hypoxic conditions. Conditioned media from neuroblastoma cells transfected with small interfering RNAs (siRNA) targeting MALAT1, compared with conditioned media from neuroblastoma cells transfected with control siRNAs, induced significantly less endothelial cell migration, invasion and vasculature formation. Microarray-based differential gene expression analysis showed that one of the genes most significantly down-regulated following MALAT1 suppression in human neuroblastoma cells under hypoxic conditions was fibroblast growth factor 2 (FGF2). RT-PCR and immunoblot analyses confirmed that MALAT1 suppression reduced FGF2 expression, and Enzyme-Linked Immunosorbent Assays revealed that transfection with MALAT1 siRNAs reduced FGF2 protein secretion from neuroblastoma cells. Importantly, addition of recombinant FGF2 protein to the cell culture media reversed the effects of MALAT1 siRNA on vasculature formation. Taken together, our data suggest that up-regulation of MALAT1 expression in human neuroblastoma cells under hypoxic conditions increases FGF2 expression and promotes vasculature formation, and therefore plays an important role in tumor-driven angiogenesis.
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors: Andrew E
authors: AE
authors: Tee
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors: Bing
authors: B
authors: Liu
authors: Advanced Analytics Institute, University of Technology, Sydney, Broadway, NSW, Australia.
authors: Renhua
authors: R
authors: Song
authors: Advanced Analytics Institute, University of Technology, Sydney, Broadway, NSW, Australia.
authors: Jinyan
authors: J
authors: Li
authors: Metronomics Global Health Initiative, Marseille, France.
authors: Eddy
authors: E
authors: Pasquier
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors: Belamy B
authors: BB
authors: Cheung
authors: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors: Cizhong
authors: C
authors: Jiang
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.|Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia.
authors: Glenn M
authors: GM
authors: Marshall
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors: Michelle
authors: M
authors: Haber
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.|Centre for Childhood Cancer Research, University of New South Wales, Sydney, Kensington, NSW, Australia.
authors: Murray D
authors: MD
authors: Norris
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors: Jamie I
authors: JI
authors: Fletcher
authors: Garvan Institute of Medical Research, Sydney, Darlinghurst, NSW, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Darlinghurst, NSW, Australia.
authors: Marcel E
authors: ME
authors: Dinger
authors: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.|Centre for Childhood Cancer Research, University of New South Wales, Sydney, Kensington, NSW, Australia.
authors: Tao
authors: T
authors: Liu
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009447:Neuroblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation
chemical_list: C557041:MALAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2
keywords: FGF2; MALAT1; angiogenesis; long noncoding RNA; neuroblastoma