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.

LncRNA as a Therapeutic Target for Angiogenesis

“…Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is another lncRNA, which plays an essential role in angiogenesis [39]. MALAT1 is significantly upregulated by hypoxia and hyperglycemia in endothelial cells [40].…”

The role of lncRNA MALAT1 in cardiovascular disease

“…57 Hypoxia could promote angiogenesis of ECs through vascular endothelial growth factor (VEGF) signaling and also induce expression of MALAT1. [58][59][60][61] MALAT1 knockdown significantly reduced the VEGF expression and the capacity for angiogenesis via inhibition of 15-lipoxygenase 1 (15-LOX1) and the phosphorylation of signal transducers and activators of transcription 3 (pSTAT3). 17…”

Functions and regulatory mechanisms of metastasis‐associated lung adenocarcinoma transcript 1

“…As one of the first identified cancer‐associated lncRNAs, MALAT1 was reported to be overexpressed in gastric cancer (Chen, Liu, Wang et al, 2017), breast cancer (Arun et al, ), prostate cancer (Ren et al, ), cervical cancer (Sun, Qin et al, ), acute myeloid leukemia (Chen, Nagel et al, 2018), medullary thyroid cancer (Chu, Hardin, Schneider, Chen, & Lloyd, ), choriocarcinoma (Shi, Wang, & Yin, ), gallbladder cancer (Sun et al, ), pancreatic cancer (Xie et al, 2017), multiple myeloma (Liu, Wang et al, ), ovarian cancer (Wu et al, 2017), T and natural killer cell lymphoma (Kim, Kim, Yang, Kim, & Yoon, ), acute monocytic leukemia (Huang, Liu et al, ), endometrial stromal sarcoma (Yamada et al, ), myeloma (Cho et al, ), clear cell renal cell carcinoma (Zhang, Yang, Chen, Che, & Zheng, ), esophageal squamous cell carcinoma (Hu et al, ), glioma (Ma, Wang, Li et al, ), osteosarcoma (Cai et al, ), neuroblastoma (Tee et al, ), tongue squamous cell carcinomas (Fang et al, ), hilar cholangiocarcinoma (Tan, Huang, & Li, ), mantle cell lymphoma (Wang, Zhu et al, ), and other tumor tissues. It has been reported that MALAT1 is involved in the regulation of tumor proliferation, apoptosis, invasion, metastasis, and angiogenesis.…”