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Mechanism of tumor-derived extracellular vesicles in prostatic cancer progression through the circFMN2/KLF2/RNF128 axis

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Abstract

Circular RNAs (circRNAs) are a major type of cargos encapsulated in extracellular vesicles (EVs) and regulate the progression of prostatic cancer (PC). This study was conducted to explore the role of tumor-derived EVs in PC cell proliferation, invasion, and migration via shuttle of circRNA formin 2 (circFMN2). RT-qPCR or Western blot assay showed that circFMN2 was upregulated while KLF2 and RNF128 were downregulated in PC tissues and cells. EVs were separated from PC cells and characterized and its internalization in PC cells was examined, which suggested that PC-EVs mediated the shuttle of circFMN2 to upregulate circFMN2 expression in PC cells. PC cell functions were determined by cell counting kit-8, colony formation and Transwell assays, which suggested that PC-EVs fueled the proliferation, invasion, and migration of PC cells. At cellular level, PC-EVs mediated the shuttle of circFMN2 to upregulate circFMN2 expression in PC cells, and circFMN2 binding to HuR decreased the HuR-KLF2 interaction and repressed KLF2 expression, which further reduced the KLF2-RNF128 promoter binding and repressed RNF128 transcription. Overexpression of KLF2/RNF128 ablated the effects of PC-EVs on the proliferation, invasion, and migration of PC cells. The xenograft tumor models and lung/liver metastasis models were established and revealed that PC-EVs accelerated tumorigenesis and metastasis in vivo via delivery of circFMN2 and repression of KLF2/RNF128.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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The authors did not receive support from any organization for the submitted work.

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Authors and Affiliations

  1. Department of Urology, The Third Medical Center of PLA General Hospital, No. 69 Yongding Road, Haidian District, Beijing, 100039, China

    Shuang Huang, Jianming Zhao, Hongkai Yu & Guangfu Chen

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  1. Shuang Huang
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  2. Jianming Zhao
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  3. Hongkai Yu
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  4. Guangfu Chen
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Contributions

SH and JZ participated in the design of the study and carried out the acquisition of data. HY and GC performed the experiment and drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guangfu Chen.

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The animal experiments were conducted under the guidance of Animal Care and Use Committee of The Third Medical Center of PLA General Hospital.

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All procedures involving human research conformed to the ethical standards of The Third Medical Center of PLA General Hospital and followed Declaration of Helsinki.

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Huang, S., Zhao, J., Yu, H. et al. Mechanism of tumor-derived extracellular vesicles in prostatic cancer progression through the circFMN2/KLF2/RNF128 axis. Apoptosis 28, 1372–1389 (2023). https://doi.org/10.1007/s10495-023-01872-y

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