Circ-MFN2 Positively Regulates the Proliferation, Metastasis, and Radioresistance of Colorectal Cancer by Regulating the miR-574-3p/IGF1R Signaling Axis.

Defeng Liu,Yangyang Li,Tao Guo,Shihao Peng

doi:10.3389/fgene.2021.671337

Abstract

Numerous studies have shown that the expression of circular RNA (circRNA) is closely related to the malignant progression of cancer. However, the role of circ-MFN2 in colorectal cancer (CRC) is unclear. Our study aims to explore the role and mechanism of circ-MFN2 in CRC progression. The relative expression levels of circ-MFN2, microRNA (miR)-574-3p and insulin-like growth factor 1 receptor (IGF1R) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was determined using 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The colony number and radioresistance of cells were assessed using colony formation assay. Moreover, the migration and invasion of cells were measured using transwell assay. Tumor xenograft model was constructed to evaluate the effect of circ-MFN2 knockdown on CRC tumor growth. Furthermore, dual-luciferase reporter assay was used to verify the interaction between miR-574-3p and circ-MFN2 or IGF1R. In addition, the protein level of IGF1R was evaluated by western blot (WB) analysis. Circ-MFN2 expression was elevated in CRC tissues and cells. Knockdown of circ-MFN2 restrained the proliferation, migration, invasion, and radioresistance of CRC cells in vitro. Furthermore, silenced circ-MFN2 also reduced the tumor volume and weight of CRC in vivo. MiR-574-3p could be sponged by circ-MFN2, and its inhibitor reversed the suppression effect of circ-MFN2 silencing on CRC progression. Moreover, IGF1R was a target of miR-574-3p, and its overexpression reversed the inhibition effect of miR-574-3p mimic on CRC progression. In addition, circ-MFN2 could positively regulate IGF1R expression by sponging miR-574-3p. Our results revealed that circ-MFN2 promoted the proliferation, metastasis and radioresistance of CRC through regulating the miR-574-3p/IGF1R axis, suggesting that circ-MFN2 might be a novel therapeutic biomarker for CRC.

Highlights

Colorectal cancer (CRC) is a common malignant tumor, which affects the digestive system, and metastasizes to the lymph, liver and kidney (Arnold et al, 2017; Siegel et al, 2018)
We found that the high expression of circ-MFN2 was associated with TNM stage, lymph node metastasis and tumor size (Table 1)
We focused on exploring the function of circ-MFN2 in colorectal cancer (CRC)

Summary

Introduction

Colorectal cancer (CRC) is a common malignant tumor, which affects the digestive system, and metastasizes to the lymph, liver and kidney (Arnold et al, 2017; Siegel et al, 2018). The occurrence of tumor metastasis and radioresistance seriously affect the prognosis of CRC patients and markedly increase the treatment difficulty of CRC (Hohla et al, 2014; Lee and Oh, 2016). Understanding the molecular mechanisms that affect the metastasis and radioresistance of CRC are critical to improve the treatment strategies of CRC. Compared with traditional linear RNA, circRNA has a closed-loop structure and more stable expression (Ebbesen et al, 2017; Belousova et al, 2018). Researches have indicated that circRNA expression is closely related to cancer progression, including CRC (Taborda et al, 2017; Cui et al, 2018). Knockdown of hsa_circ_0001313 could inhibit the radioresistance of colon cancer by sponging miR-338-3p (Wang L. et al, 2019)

Methods

Results

Conclusion