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: Andrew E Tee, Bing Liu, Renhua Song, Jinyan Li, Eddy Pasquier, Belamy B Cheung, Cizhong Jiang, Glenn M Marshall, Michelle Haber, Murray D Norris, Jamie I Fletcher, Marcel E Dinger, Tao Liu
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 8 Pg. 8663-75 (Feb 23 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26848616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MALAT1 long non-coding RNA, human
• RNA, Long Noncoding
• RNA, Messenger
• Fibroblast Growth Factor 2

Topics

• Apoptosis
• Blotting, Western
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• Fibroblast Growth Factor 2 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Human Umbilical Vein Endothelial Cells (cytology, metabolism)
• Humans
• Immunoenzyme Techniques
• Neovascularization, Pathologic (genetics)
• Neuroblastoma (blood supply, metabolism, pathology)
• RNA, Long Noncoding (genetics)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Transcriptional Activation