Circ_0004585 Facilitates Tumorigenesis of Colorectal Cancer Via Modulating the miR-338-3p/ZFX Axis and Activating the MEK/ERK Pathway,Cellular and Molecular Bioengineering

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Circ_0004585 Facilitates Tumorigenesis of Colorectal Cancer Via Modulating the miR-338-3p/ZFX Axis and Activating the MEK/ERK Pathway
Cellular and Molecular Bioengineering ( IF 2.3 ) Pub Date : 2023-01-20 , DOI: 10.1007/s12195-022-00756-6
Zenghai Lin ₁ , Jianwei Lin ₁

Affiliation

Background

Colorectal cancer (CRC) is a common malignant tumor in the digestive tract. Circular RNAs (circRNAs) have been identified as crucial regulators of tumorigenesis. However, the role and potential mechanism of circ_0004585 in CRC are poorly understood.

Methods

The expression of circ_0004585, microRNA-338-3p (miR-338-3p), and zinc finger protein X-linked (ZFX) was detected by quantitative real-time PCR and Western blot. Cell proliferation, cell cycle arrest, apoptosis, and angiogenesis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), 5-Ethynyl-2′-deoxyuridine (EdU), flow cytometry and tube formation assays. Western blot assay was applied to detect the expression of epithelial-mesenchymal transition (EMT)-related proteins and MEK/ERK signaling pathway-related proteins. A xenograft model was used to analyze tumor growth in vivo. The targeted relationship between miR-338-3p and circ_0004585/ZFX was verified by a dual-luciferase reporter assay.

Results

Circ_0004585 and ZFX were up-regulated, while miR-338-3p was down-regulated in CRC tissues and cells. Silencing of circ_0004585 inhibited proliferation, angiogenesis, and EMT and triggered apoptosis in CRC cells. Consistently, circ_0004585 depletion blocked tumor growth in vivo. Circ_0004585 contributed to CRC cell development via sequestering miR-338-3p. Also, miR-338-3p hindered the malignant progression of CRC cells by targeting ZFX. Circ_0004585 activated MEK/ERK pathway via regulating ZFX.

Conclusion

Circ_0004585 facilitated CRC progression through modulating miR-338-3p/ZFX/MEK/ERK pathway, which might provide a potential therapeutic target for CRC.

中文翻译：

Circ_0004585 通过调节 miR-338-3p/ZFX 轴和激活 MEK/ERK 通路促进结直肠癌的肿瘤发生

背景

结直肠癌（CRC）是消化道常见的恶性肿瘤。环状RNA（circRNA）已被确定为肿瘤发生的关键调节因子。然而，人们对 circ_0004585 在 CRC 中的作用和潜在机制知之甚少。

方法

通过实时定量PCR和Western blot检测circ_0004585、microRNA-338-3p (miR-338-3p)和锌指蛋白X-linked (ZFX)的表达。通过 3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-四唑溴化物 (MTT)、5-乙炔基-2' 评估细胞增殖、细胞周期停滞、凋亡和血管生成-脱氧尿苷（EdU）、流式细胞术和管形成测定。采用Western blot法检测上皮间质转化（EMT）相关蛋白和MEK/ERK信号通路相关蛋白的表达。使用异种移植模型来分析体内肿瘤生长。通过双荧光素酶报告基因测定验证了 miR-338-3p 和 circ_0004585/ZFX 之间的靶向关系。

结果

在 CRC 组织和细胞中，Circ_0004585 和 ZFX 上调，而 miR-338-3p 下调。 circ_0004585 的沉默抑制了 CRC 细胞的增殖、血管生成和 EMT，并引发细胞凋亡。一致地，circ_0004585耗竭阻止了体内肿瘤生长。 Circ_0004585通过隔离 miR-338-3p 促进 CRC 细胞发育。此外，miR-338-3p通过靶向ZFX阻碍CRC细胞的恶性进展。 Circ_0004585通过调节ZFX激活MEK/ERK通路。