Circular RNA GLIS2 promotes colorectal cancer cell motility via activation of the NF-\u03baB pathway

Junxiong Chen,Zefeng Zhu,Chuangyu Wen,Huihui Wang,Weiqian Li,Xiangling Yang,Lanlan Huang,Yonglin Zhu,Huanliang Liu,Ruixian Liu

doi:10.1038/s41419-020-02989-7

Abstract

Circular RNAs (circRNAs) are a newly discovered type of biological molecule that belongs to the noncoding RNA family. Abundant evidence has shown that circRNAs are involved in the progression of various cancers. However, the particular functions of circRNAs in colorectal cancer (CRC) remain elusive. In this study, we investigated the differentially expressed circRNAs in three pairs of cancer tissue and adjacent normal tissue of CRC. We revealed that circGLIS2 expression was higher in CRC tissue and cell lines. Gain-and-loss function assays showed that circGLIS2 was involved in the regulation of cell migration. Moreover, overexpressing circGLIS2 in CRC cells activated the NF-κB pathway and induced pro-inflammatory chemokine production, which evoked tumor-associated inflammation through recruiting leukocytes. In turn, when the cancer cells were exposed to the supernatant of circGLIS2 overexpressed cancer cells, they were endowed with the ability of migration and chemokines production. Furthermore, the rescue assay confirmed that circGLIS2 activated NF-κB signaling and promoted cell migration by sponging miR-671. Overall, our study reveals that circGLIS2, acting as a potential oncogene, maintains the abnormal activation state of the NF-κB signaling pathway via the miR-671 sponge mechanism in CRC cells. This study provides a scientific basis for targeting circGLIS2 in colorectal cancer interventions.

Highlights

Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of death in cancers around the world[1]
CircRNAs act as miRNAs sponges to regulate the expression of target genes via the miRNAs response element[8,9]. This notion has been supported by a series of previous studies: circPVT1 functions as an oncogene to promote metastasis via miR-145 sponging in CRC10; circPDE8A promotes the invasive growth of pancreatic ductal adenocarcinoma cells by antagonizing miR-338 to enhance the MET pathway[11]; and fibroblast growth factor receptor 1 (FGFR1) derived circular RNA circFGFR1 promotes non-small cell lung cancer progression and resistance to immune checkpoint inhibitor therapy via miR-381-3p/ CXCR4 axis[12]
CircGLIS2 sponge miR-671 to modulate NF-κB signaling pathway and enhance the motility of CRC cells. These results indicated that circGLIS2/miR-671/NF-κB pathway axis regulated metastasis function via an autocrine-paracrine manner in CRC, which may be a promising target for CRC intervention

Summary

Introduction

Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of death in cancers around the world[1]. Circular RNAs (circRNAs), characterized by their back-spliced ring structure, are widely expressed in eukaryotes[3,4]. CircRNAs are more stable than other kinds of RNAs, because of their tolerance of exonucleases. CircRNAs act as miRNAs sponges to regulate the expression of target genes via the miRNAs response element[8,9]. This notion has been supported by a series of previous studies: circPVT1 functions as an oncogene to promote metastasis via miR-145 sponging in CRC10; circPDE8A promotes the invasive growth of pancreatic ductal adenocarcinoma cells by antagonizing miR-338 to enhance the MET pathway[11]; and fibroblast growth factor receptor 1

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Results

Conclusion