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

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.

SUBMITTER: Liu D

PROVIDER: S-EPMC8170135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:The development of radioresistance remains the obstacle for prostate cancer (PCa) treatment. Here, we explored the role and potential mechanism of circular RNA zinc finger protein 609 (circ-ZNF609) in the radioresistance of PCa cells. Materials and Methods:Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circ-ZNF609, microRNA-501-3p (miR-501-3p) and hexokinase 2 (HK2) messenger RNA (mRNA). The viability, apoptosis, metastasis and radioresistance of PCa cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, transwell assays and colony formation assay. The glycolytic rate was assessed through measuring the glucose consumption and lactate production using fluorescence-based glucose and lactate assay kits. The target interaction between miR-501-3p and circ-ZNF609 or HK2 was predicted by StarBase software and confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The protein level of HK2 was detected by Western blot assay. In vivo tumor growth assay was used to explore the role of circ-ZNF609 in the radioresistance of PCa in vivo. Results:Circ-ZNF609 was abnormally up-regulated in PCa tissues and cell lines. Circ-ZNF609 silencing hampered the viability, metastasis, radioresistance and promoted the apoptosis through suppressing cell glycolysis. MiR-501-3p was a direct target of circ-ZNF609, and si-circ-ZNF609-induced influence in PCa cells was partly alleviated by the addition of anti-miR-501-3p. MiR-501-3p functioned through directly interacting with and down-regulating HK2. HK2 was modulated by circ-ZNF609/miR-501-3p axis in PCa cells. Circ-ZNF609 silencing enhanced the radiosensitivity of PCa cells in vivo. Conclusion:Circ-ZNF609 promoted the progression and radioresistance of PCa cells through accelerating the glycolysis via miR-501-3p/HK2 axis, providing promising targets for improving the prognosis of PCa patients.

Project description:BackgroundDrug-resistance is a major obstacle to the treatment of breast cancer. Circular RNA (circRNA) circ-MMP11 has been reported to be promoting the progression of breast cancer. This study is designed to explore the role and mechanism of circ-MMP11 in lapatinib resistance in breast cancer.MethodsCirc-MMP11, microRNA-153-3p (miR-153-3p), and Anillin (ANLN) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, number of colonies, apoptosis, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. Exosomes were exerted and detected by differential centrifugation and a transmission electron microscope. The protein levels of CD63, CD9, and ANLN were assessed by western blot assay. The binding relationship between miR-153-3p and circ-MMP11 or ANLN was predicted by circinteractome or starbase, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. The biological role of circ-MMP11 on breast cancer tumor growth and drug resistance was detected by the xenograft tumor model in vivo.ResultsCirc-MMP11 and ANLN were highly expressed, and miR-153-3p was decreased in LR breast cancer tissues and cells. Circ-MMP11 could be transported by exosomes. Furthermore, circ-MMP11 knockdown promoted lapatinib sensitivity by repressing cell viability, colony number, migration, invasion, and boosting apoptosis in LR breast cancer cells. Circ-MMP11 deficiency improved the drug sensitivity of breast cancer in vivo. Mechanically, circ-MMP11 could regulate ANLN expression through sponging miR-153-3p.ConclusionCirc-MMP11 could be transferred by exosomes in breast cancer cells. And circ-MMP11 functioned as a sponge of miR-153-3p to regulate ANLN expression, thereby promoting lapatinib resistance in breast cancer cells, providing therapeutic targets for the treatment of breast cancer.

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

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