Oncotarget

Research Papers:

The long noncoding RNA MALAT1 promotes tumor-driven angiogenesis by up-regulating pro-angiogenic gene expression

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 and Tao Liu _

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Oncotarget. 2016; 7:8663-8675. https://doi.org/10.18632/oncotarget.6675

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Abstract

Andrew E. Tee1, Bing Liu1, Renhua Song2, Jinyan Li2, Eddy Pasquier3, Belamy B. Cheung1, Cizhong Jiang4, Glenn M. Marshall1,5, Michelle Haber1, Murray D. Norris1,6, Jamie I. Fletcher1, Marcel E. Dinger7,8, Tao Liu1,6

1Children’s Cancer Institute Australia for Medical Research, Randwick, NSW, Australia

2Advanced Analytics Institute, University of Technology, Sydney, Broadway, NSW, Australia

3Metronomics Global Health Initiative, Marseille, France

4Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

5Kids Cancer Centre, Sydney Children’s Hospital, Randwick, NSW, Australia

6Centre for Childhood Cancer Research, University of New South Wales, Sydney, Kensington, NSW, Australia

7Garvan Institute of Medical Research, Sydney, Darlinghurst, NSW, Australia

8St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Darlinghurst, NSW, Australia

Correspondence to:

Tao Liu, e-mail: tliu@ccia.unsw.edu.au

Keywords: long noncoding RNA, MALAT1, angiogenesis, neuroblastoma, FGF2

Received: September 03, 2015     Accepted: December 07, 2015     Published: February 2, 2016

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.


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