CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling

Jing Zhang,Jinshui Zhu,Rui Zhang,Wei Chen,Lidan Hou,Rui Liang,Xiaoyu Chen

doi:10.1186/s12943-019-1015-1

Abstract

BackgroundAccumulating evidence shows that, the dysregulation of circular RNAs (circRNAs) is associated with the progression of multiple malignancies. But, the underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented.MethodsThe expression and cellular localization of circDLST and its association with clinicopathological characteristics and prognosis in patients with GC was analysed by using fluorescence in situ hybridization. Gain- and loss-of-function experiments as well as a subcutaneous xenograft tumor model and a liver metastasis model from orthotopic implantation of GC tissues were conducted to assess the role of circDLST in GC cells. CircDLST specific binding with miR-502-5p was confirmed by dual luciferase gene report, RNA immunoprecipitation (RIP) assays and RIP-miRNA expression profiling. qRT-PCR and Western blot analysis was used to detect the effects of circDLST on miR-502-5p-mediated NRAS/MEK1/ERK1/2 signaling in GC cells.ResultsThe expression levels of circDLST were dramatically elevated in GC tissues as compared with the adjacent normal tissues, and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDLST inhibited the cell viability, colony formation, DNA synthesis, cell invasion and liver metastasis in vitro and in vivo, whereas overexpression of circDLST had the opposite effects. Furthermore, circDLST was co-localized with miR-502-5p in the cytoplasm of GC cells, and acted as a sponge of miR-502-3p in GC cells, which abrogated the tumor promoting effects of circDLST by inactivating the NRAS/MEK1/ERK1/2 signaling in GC cells.ConclusionCircDLST promotes the tumorigenesis and metastasis of GC cells by sponging miR-502-5p to activate the NRAS/MEK1/ERK1/2 signaling.

Highlights

The incidence and mortality of gastric cancer (GC) rank the fifth place in tumors of digestive system worldwide [1] and it is the third leading cause of cancer-related deaths in China [2]
High expression of circDLST was associated with poor survival in patients with GC We previously confirmed an antitumor effect of toosendanin in GC cells [26], and identified a novel has_circ_0032627 derived from the linear gene dihydrolipoamide S-succinyltransferase (DLST) as a key target of toosendanin in GC cells
The expression levels of circDLST in GC tissues were detected by using Fluorescence in situ hybridization (FISH) analysis, indicated that, circDLST expression levels were strikingly increased in GC tissues as compared with the adjacent normal tissues (n = 71, P = 0.0079; Fig. 1a), and predominantly localized in the cytoplasm of GC tissue cells (Fig. 1b)

Summary

Introduction

The incidence and mortality of gastric cancer (GC) rank the fifth place in tumors of digestive system worldwide [1] and it is the third leading cause of cancer-related deaths in China [2]. Circular RNAs (circRNAs), a new class of ncRNAs, have a covalently closed loop, display a tissue specific expression and are highly conserved owing to their resistance to RNase R [8]. They interact with RNA binding proteins involved in. Circ_0000520, circLARP4 and circPVT1 have been identified as potential biomarkers for predicting the survival of patients with GC [19,20,21]. They act as oncogenes or tumor suppressors in GC cells. The underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented

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Discussion

Conclusion