Background

Circβ-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown.

Methods

The qRT-PCR examination was used to detect the expression of circβ-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circβ-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circβ-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circβ-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays.

Results

In the present study, circβ-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circβ-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circβ-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2.

Conclusions

Our findings illustrated a novel mechanism of circβ-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.

中文翻译：

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EIF4A3负驱动的环状RNA β-连环蛋白（circβ-catenin）通过miR-197-3p/CTNND1调节轴促进结直肠癌进展

背景

Circβ-连环蛋白是我们第一个报道的 circRNA，据报道可介导各种癌症的肿瘤发生。然而，其在结直肠癌（CRC）中的生物学功能和潜在机制仍不清楚。

方法

采用qRT-PCR检测细胞和人体组织中circβ-catenin、miR-197-3p和CTNND1的表达。采用Western blot检测蛋白表达水平。通过 MTT、集落形成、伤口愈合和 Transwell 实验验证了 circβ-catenin 的生物学功能。通过裸鼠异种移植和转移模型验证了circβ-catenin的体内作用。通过双荧光素酶报告基因和 RIP 检测证实了 circβ-catenin/miR-197-3p/CTNND1 的调控网络。

结果

在本研究中，发现circβ-catenin在体外和体内促进CRC细胞增殖和转移。从机制上讲，circβ-catenin作为miRNA诱饵直接与miR-197-3p结合，然后拮抗靶基因CTNND1的抑制，最终促进CRC的恶性表型。更有趣的是，被称为 AluJb1/2 和 AluY 的反向重复 Alu 对促进了 circβ-catenin 的生物发生，而 EIF4A3 与 Alu 元件 AluJb2 的结合可以部分逆转这种情况。

结论

我们的研究结果阐明了环β-连环蛋白调节结直肠癌肿瘤发生和转移的新机制，为结直肠癌患者提供了潜在的治疗靶点。