Circular RNA UBE2Q2 promotes malignant progression of gastric cancer by regulating signal transducer and activator of transcription 3-mediated autophagy and glycolysis

Jing Yang,Zekuan Xu,Li Xie,Jiacheng Cao,Lang Fang,Lu Zhang,Bowen Li,Penghui Xu,Sen Wang,Xing Zhang,Zetian Chen

doi:10.1038/s41419-021-04216-3

Abstract

Gastric cancer remains the third leading cause of cancer-related mortality worldwide. Emerging evidence has shown that circular RNAs (circRNAs) play a critical regulatory role in the occurrence and development of various cancers through sponging miRNAs or acting as RNA-binding protein (RBP) sponges. We found that circUBE2Q2 was significantly upregulated in GC tissues and cell lines. Knockdown of circUBE2Q2 inhibited proliferation, migration, invasion, and glycolysis, and increased autophagy in vitro. In addition, knockdown of circUBE2Q2 inhibited GC tumorigenicity and metastasis potential in vivo. A series of experiments were performed to confirm that circUBE2Q2 regulates GC progression via the circUBE2Q2-miR-370-3p-STAT3 axis and promotes tumor metastasis through exosomal communication. Further in vivo experiments confirmed that, combination treatment of circUBE2Q2 knocking down and STAT3 inhibitor has synergistic effects on the gastric cancer growth inhibition, which provides a possibility to enhance the sensitivity of targeted drugs to gastric cancer through targeting circUBE2Q2. Our findings revealed that circUBE2Q2 may serve as a new proliferation-promoting factor and prognostic marker in gastric cancer.

Highlights

Gastric cancer (GC) is the fifth most common cancer and malignant tumor, which ranks as the third leading cause of cancer-related mortality worldwide according to the GLOBOCAN database [1]
We only found the enrichment of circUBE2Q2 and in the luciferase signal caused by cotransfection of the wild-type miR-370-3p in both MKN-45 and BGC-823 cells compared with the circUBE2Q2 reporter genes and miR-370-3p mimics, no significant interactions between the other miRNAs and circUBE2Q2 (Fig. 3C changes were observed after cotransfection of the mut3 and Supplementary Fig. 1D)
The PACS1 and signal transducer and activator of transcription 3 (STAT3) expression levels exhibited a clear negative correlation with miR-370-3p, whereas we found no such correlation for PARVB (Fig. 4D and Supplementary Fig. 3G–H). quantitative real-time PCR (qRT-PCR) results indicated that STAT3 expression was significantly upregulated in both MKN-45 and BGC-823 cells transfected with miR-370-3p inhibitors (Fig. 4E and Supplementary Fig. 3I)

Summary

Introduction

Gastric cancer (GC) is the fifth most common cancer and malignant tumor, which ranks as the third leading cause of cancer-related mortality worldwide according to the GLOBOCAN database [1]. Investigation of the underlying molecular mechanisms of the malignant progression of GC is of great concern for improving the survival of patients and reducing the recurrence rate. MicroRNAs (miRNAs) are a class of noncoding single-stranded RNA molecules with a length of about 22 nucleotides encoded by endogenous genes, which are involved in the regulation of posttranscriptional gene expression [11]. Emerging evidence suggests that circRNA can function as miRNAs sponges to regulate downstream genes in tumors [5, 12]. It has been reported that some circRNAs can act as RNA-binding protein (RBP) sponges or function as protein translation [12,13,14]. The potential mechanism of circRNA regulating the malignant behavior of GC is still unclear and deserves further investigation

Methods

Results

Conclusion