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Translational Therapeutics

EIF4A3-negatively driven circular RNA β-catenin (circβ-catenin) promotes colorectal cancer progression via miR-197-3p/CTNND1 regulatory axis

British Journal of Cancer (2024)Cite this article

Subjects

Abstract

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.

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Fig. 1: Characterization of circβ-catenin in CRC cells.
Fig. 2: Circβ-catenin promoted the proliferation and metastasis in vitro and in vivo.
Fig. 3: Circβ-catenin acted as a miRNA decoy for miR-197-3p in CRC cells.
Fig. 4: CTNND1 was the direct target for miR-197-3p.
Fig. 5: Circβ-catenin stimulated CRC cell proliferation and metastasis via targeting miR-197-3p.
Fig. 6: EIF4A3 negatively regulated the biogenesis of circβ-catenin through interacting with the Alu element.

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Funding

This work was supported by the Futian Healthcare Research Project (FTWS2023065), the National Natural Science Foundation of China (No. 82772526) and the Natural Science Foundation of Guangdong Province (2020A1515010961, 2021A1515012111).

Author information

Author notes

  1. These authors contributed equally: Li-Qiang Deng, Chuan-Jian Shi.

Authors and Affiliations

  1. Cancer center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, China

    Li-Qiang Deng, Chuan-Jian Shi, Yu-Yan Wang & Jin-Fang Zhang

  2. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China

    Li-Qiang Deng, Chuan-Jian Shi, Wei-Qiang Zeng & Wei-Ming Fu

  3. Research Institute, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518000, China

    Li-Qiang Deng, Chuan-Jian Shi, Han-Li Lin & Jin-Fang Zhang

  4. Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Shu-Ting Zhou, Wei Liu & Jin-Fang Zhang

  5. School of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China

    Yan-Fang Xian

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Contributions

HL and JZ conceived and designed the whole project and the experiments. LD, CS, SZ, and WL conducted the experiments. YX, YW, WF, WZ, and LD performed data analysis. CS and LD wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Han-Li Lin, Wei Liu or Jin-Fang Zhang.

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The protocol was approved by Ethics Committee from Sun Yat-sen University approved this study, and patient consent was obtained before the samples were taken. The usage and treatment of animals were approved by Institutional Animal Care and Use Committee (IACUC) of Southern Medical University.

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Deng, LQ., Shi, CJ., Zhou, ST. et al. EIF4A3-negatively driven circular RNA β-catenin (circβ-catenin) promotes colorectal cancer progression via miR-197-3p/CTNND1 regulatory axis. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02612-y

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