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Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway

Cancer Gene Therapy volume 30, pages 437–449 (2023)Cite this article

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Abstract

Bone metastasis is the most common complication responsible for most deaths in the advanced stages of prostate cancer (PCa). However, the exact mechanism of bone metastasis in PCa remains unelucidated. Herein, we explored the function and potential underlying mechanism of exosomal miR-375 in bone metastasis and tumor progression in PCa. This study revealed that miR-375 expression was markedly upregulated in advanced PCa with bone metastasis and metastatic PCa cell lines. Moreover, miR-375 showed high expression in PCa-derived exosomes and could be delivered to human mesenchymal stem cells (hMSCs) via exosomes. Mechanistically, miR-375 directly targeted DIP2C and upregulated the Wnt signaling pathway, thereby promoting osteoblastic differentiation in hMSCs. Furthermore, miR-375 promoted the proliferation, invasion, and migration of PCa cells in vitro and enhanced tumor progression and osteoblastic metastasis in vivo. Notably, the expression of miR-375, TCF-1, LEF-1, and β-catenin in was higher in PCa tissues with bone metastasis than in PCa tissues without bone metastasis and showed a continuous increase, whereas DIP2C, cyclin D1, and Axin2 showed an opposite expression pattern. In conclusion, our study suggests that cancer-derived exosomal miR-375 targets DIP2C, activates the Wnt signaling pathway, and promotes osteoblastic metastasis and PCa progression.

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Fig. 1: Cancer-derived miR-375 is transferred via exosomes to human mesenchymal stem cells.
Fig. 2: Cancer-secreted miR-375 promotes the osteoblastic differentiation of hMSCs.
Fig. 3: DIP2C is target of miR-375 to promote osteoblastic differentiation in hMSCs.
Fig. 4: Cancer-secreted miR-375 promotes osteoblastic differentiation of hMSCs through Wnt signaling.
Fig. 5: miR-375 enhances proliferation, migration, and invasion of PCa cells.
Fig. 6: miR-375 promotes progression and metastasis of PCa in vivo.
Fig. 7: Correlation of miR-375 with DIP2C and Wnt signaling pathway in human PCa tissues.
Fig. 8: The mechanism scheme of exosomal miR-375 promoting PCa progression and bone.

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Data availability

All data included in this study are available upon request by contact with the corresponding author.

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Funding

The work was funded by the President Foundation of Nanfang Hospital, Southern Medical University [grant number: 2020B025].

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Author notes

  1. These authors contributed equally: Ying Liu, Changmou Yang, Shisheng Chen.

Authors and Affiliations

  1. Department of Oncology, Affiliated Huadu Hospital, Southern Medical University (People’s Hospital of Huadu District), Guangzhou, 510810, Guangdong, China

    Ying Liu

  2. Department of Urology, Shenshan Central Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei, 516600, Guangdong, China

    Changmou Yang

  3. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Changmou Yang, Shisheng Chen, Weihao Liu, Jingyi Liang & Shuhua He

  4. Department of Urology, Dongguan Tungwah Hospital, Dongguan, 523110, Guangdong, China

    Shisheng Chen

  5. Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Jialiang Hui

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Contributions

HSH: Conceptualization; LY and YCM: Methodology; HSH: Validation; LY, YCM, CSS, and LWH: Investigation; YCM and CSS: Resources; YCM: Writing - original draft; CSS and LJY: Writing - review & editing; CSS and LJY: Visualization; LY and LJY: Supervision; HJL: Project administration; HJL and HSH: Funding acquisition.

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Correspondence to Shuhua He or Jialiang Hui.

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All mouse experiments were approved by the Nanfang Hospital Animal Ethics Committee (approval no. NFYY-2019-1227).

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Liu, Y., Yang, C., Chen, S. et al. Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway. Cancer Gene Ther 30, 437–449 (2023). https://doi.org/10.1038/s41417-022-00563-1

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