Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877–3p to facilitate gastric cancer invasion and metastasis

Highlights

• Circ-RanGAP1 is up regulated in gastric cancer (GC) tissues and plasma exosomes.

• Circ-RanGAP1 overexpression is correlated with poor prognosis in GC.

• Circ-RanGAP1 promotes GC invasion and metastasis both in vitro and in vivo.

• Circ-RanGAP1 promotes GC progression through miR-877–3p/VEGFA axis.

• Exosomal circ-RanGAP1 may be a promising application in GC diagnosis and treatment.

Abstract

The biological functions of circular RNAs (circRNAs) in gastric cancer (GC) remain largely unexplored. Here, we identified that circ-RanGAP1 was significantly upregulated in both GC tissues and exosomes from the plasma of GC patients. High circ-RanGAP1 expression was closely associated with an advanced TNM stage, lymph node metastases, and worse survival. Inhibition of circ-RanGAP1 decreased GC cell invasion and migration in vitro. Overexpression of circ-RanGAP1 had the opposite effect. Additionally, circ-RanGAP1 silencing remarkably suppressed tumor growth and metastasis of GC in vivo. Mechanistically, circ-RanGAP1 sponged miR-877–3p to upregulate VEGFA expression. Overexpression of miR-877–3p reversed the biological functions mediated by circ-RanGAP1 in GC cells. Interestingly, we demonstrated that circ-RanGAP1 was upregulated in plasma exosomes from preoperative GC patients. More importantly, the plasma exosomes derived from these patients enhanced the migration and invasion potential of GC cells. Overall, the circ-RanGAP1-mediated miR-877–3p/VEGFA axis promotes GC progression. Our findings suggest that circ-RanGAP1 might act as a potential prognostic biomarker and therapeutic target for GC treatment.

Introduction

Gastric cancer (GC) is a major malignant tumor and is the second leading cause of cancer death and the fifth most common cancer in the world [1,2]. The important factors that affect the prognosis of gastric cancer and lead to treatment failure are tumor invasion and metastasis [3]. Therefore, for the treatment of gastric cancer, it is important to actively explore the mechanisms of invasion and metastasis of GC.

Circular RNA (circRNA) exists in eukaryotic cells as a covalently closed loop without 5′-3′ polarity or a polyadenylated tail and has better stability and conservation compared with linear RNA [4]. There is mounting evidence that circRNAs participate in various pathological processes, such as proliferation, invasion, and metastasis, of various malignancies, including esophageal cancer [5], bladder cancer [6], breast cancer [7], pancreatic cancer [8], and so on. In GC, several circRNAs have been indicated to regulate tumor progression [9,10]; however, the role of circRNAs in GC remains far from clear.

Exosomes are membrane vesicles of endocytic origin with diameters ranging from 30 to 100 nm that can transfer specific proteins or nuclear acids to recipient cells in the local tumor environment or distant metastatic sites as a mechanism of intercellular communication [11]. Recently, many studies have reported that exosomes are involved in tumorigenesis, tumor invasion and metastasis. Different proteins, miRNAs [12], lncRNAs [13], and circRNAs [14] in exosomes have been found to be correlated with tumor progression. However, the pattern and potential role of circRNAs in both tissues and plasma exosomes of GC patients have not been definitively elucidated.

In this study, circ-RanGAP1, which has yet to be characterized in cancer, was newly identified by circRNA microarray analysis in both GC tissues and plasma exosomes from the preoperative plasma of GC patients. We found that circ-RanGAP1 was significantly upregulated in GC tissues, significantly increased in plasma exosomes of GC patients compared to those of healthy controls, and positively correlated with the tumor stage of GC. More importantly, we found that circ-RanGAP1, as a competing endogenous RNA (ceRNA) for miR-877–3p, promoted invasion and metastasis, at least partly, via the VEGFA pathway in GC. Our findings reveal a novel mechanism involving circ-RanGAP1 in GC progression.