Circular RNA circCTNNA1 promotes colorectal cancer progression by sponging miR-149-5p and regulating FOXM1 expression

Pengju Chen,Yuanyuan Kong,Yunfeng Yao,Nan Yang,Aiwen Wu,Lifei Gong

doi:10.1038/s41419-020-02757-7

Abstract

Circular RNAs (circRNAs) are an emerging class of non-coding RNAs, identified to participate in multiple malignancies. Nevertheless, the clinical significance, biological function, and regulatory mechanisms of circRNAs in colon cancer (CC) remain largely unclear. In this study, the circRNA expression profile in CC and matched normal tissues was analyzed using circRNA microarrays. A novel circRNA, circCTNNA1, was significantly upregulated in CC, and its level was associated with advanced tumor–node–metastasis stage and poor prognosis of patients with CC. Functional experiments, including Cell Counting Kit-8, colony formation, 5‐ethynyl‐2′‐deoxyuridine, transwell, wound healing, flow cytometric analysis, and in vivo tumorigenesis assay were then performed to investigate the oncogenic role of circCTNNA1. The results revealed that circCTNNA1 promoted CC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, RNA pull-down, RNA immunoprecipitation, dual-luciferase reporter assays, and fluorescent in situ hybridization were performed to unveil that circCTNNA1 can serve as a competing endogenous RNA of miR-149-5p to counteract the suppressive effect of miR-149-5p on downstream target Forkhead Box M1 (FOXM1). In summary, our study demonstrated that circCTNNA1 facilitated CC proliferation and invasion via the circCTNNA1/miR-149-5p/FOXM1 axis, and it might function as a novel diagnostic or therapeutic target for patients with CC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and second leading cause of cancer death globally[1]
We first identified that the novel circRNA circCTNNA1, which is derived from the CTNNA1 gene, is upregulated in colon cancer tissues and cell lines and promotes colon cancer progression via sponging miR-149-5p and upregulating FOXM1
CircRNA and mRNA expression profiling in colon cancer CircRNA and messenger RNA microarray analyses were applied in paired colon cancer tissues and adjacent normal tissues from three patients with colon cancer (Fig. 1a, b)

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and second leading cause of cancer death globally[1]. Colon cancer prognosis remains poor because of its distant metastasis and local recurrence[3]. It is a matter of great urgency for clinicians and researchers to develop more efficient molecular targets and novel biomarkers for colon cancer therapy and diagnosis. It has been reported that circRNAs regulate gene expression through multiple mechanisms, including sponging microRNAs (miRNAs), interacting with RNA-binding proteins, and serving as translation templates[7]. CircRNAs are predominately detected in the cytoplasm and function as miRNA sponges to regulate the expression of genes targeted by miRNAs8. Shi et al suggested that circPRKCI facilitates esophageal cancer proliferation via sponging miR-3680-3p and promotes AKT3 expression[9]

Methods

Results

Conclusion