Circ_0004676 exacerbates triple-negative breast cancer progression through regulation of the miR-377-3p/E2F6/PNO1 axis,Cell Biology and Toxicology

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Circ_0004676 exacerbates triple-negative breast cancer progression through regulation of the miR-377-3p/E2F6/PNO1 axis
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-07-23 , DOI: 10.1007/s10565-022-09704-6
Guoli Shao ₁ , Xulong Fan ₂ , Pusheng Zhang ₃ , Xuewen Liu ₁ , Lei Huang ₃ , Shufeng Ji ₁

Affiliation

Background

The significant roles of circular RNAs (circRNAs) in different cancers and diseases have been reported. We now focused on the possible role of a newly recognized circRNA, circ_0004674 in triple-negative breast cancer (TNBC), and the related downstream mechanism.

Methods

The expression of circ_0004674 in TNBC tissues and cells was determined followed by analysis of the correlation between circ_0004674 and TNBC patients’ prognosis. The interaction between circ_0004674, miR-377-3p, E2F6, and PNO1 was then identified using bioinformatics analysis combined with FISH, RIP, RNA pull-down, RT-qPCR, and Western blot analysis. Using gain-of-function and loss-of-function methods, we analyzed the effect of circ_0004674, miR-377-3p, E2F6, and PNO1 on TNBC in vivo and in vitro.

Results

Increased circ_0004674 and E2F6 but decreased miR-377-3p were observed in TNBC tissues and MDA-MB-231 TNBC cells, all of which findings were associated with poor prognosis in patients with TNBC. Silencing of circ_0004676 remarkably suppressed the proliferation, cell cycle progression, and migration of TNBC cells in vitro, as well as inhibiting tumorigenesis and metastasis in vivo. Additionally, circ_0004676 served as a sponge of miR-377-3p which bound to the transcription factor E2F6. In the presence of overexpression of circ_0004676, E2F6 expression and its target PNO1 expression were elevated, while miR-377-3p expression was decreased. Interestingly, overexpression of E2F6 could reverse the inhibitory effect on tumor growth caused by downregulation of circ_0004676.

Conclusion

Our study highlighted the carcinogenic effect of circ_0004676 on TNBC through regulation of the miR-377-3p/E2F6/PNO1 axis.

Graphical abstract

1. Circ_0004674 is highly expressed in TNBC tissues and cells.

2. Circ_0004674 upregulates the expression of E2F6 by sponging miR-377-3p.

3. E2F6 upregulates PNO1 by binding to the PNO1 promoter.

4. Circ_0004674 favors TNBC progression by regulating the miR-377-3p/E2F6/PNO1 axis.

5. This study provides a new target for the treatment of TNBC.

中文翻译：

Circ_0004676 通过调节 miR-377-3p/E2F6/PNO1 轴加剧三阴性乳腺癌进展

背景

环状 RNA (circRNA) 在不同癌症和疾病中的重要作用已有报道。我们现在重点关注新识别的circRNA circ_0004674在三阴性乳腺癌（TNBC）中的可能作用以及相关的下游机制。

方法

测定TNBC组织和细胞中circ_0004674的表达情况，分析circ_0004674与TNBC患者预后的相关性。然后使用生物信息学分析结合 FISH、RIP、RNA pull-down、RT-qPCR 和蛋白质印迹分析来鉴定 circ_0004674、miR-377-3p、E2F6 和 PNO1 之间的相互作用。使用功能获得和功能丧失方法，我们分析了 circ_0004674、miR-377-3p、E2F6 和 PNO1 对体内和体外 TNBC 的影响。

结果

在 TNBC 组织和 MDA-MB-231 TNBC 细胞中观察到 circ_0004674 和 E2F6 增加，但 miR-377-3p 减少，所有这些发现都与 TNBC 患者的不良预后相关。沉默circ_0004676可显着抑制体外TNBC细胞的增殖、细胞周期进程和迁移，并抑制体内肿瘤发生和转移。此外，circ_0004676充当与转录因子E2F6结合的miR-377-3p的海绵。在circ_0004676过表达的情况下，E2F6表达及其靶标PNO1表达升高，而miR-377-3p表达降低。有趣的是，E2F6的过度表达可以逆转circ_0004676下调引起的对肿瘤生长的抑制作用。