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Cancer-associated fibroblast exosomes promote prostate cancer metastasis through miR-500a-3p/FBXW7/HSF1 axis under hypoxic microenvironment

Cancer Gene Therapy (2024)Cite this article

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Abstract

Metastasis is the main cause of deaths in prostate cancer (PCa). However, the exact mechanisms underlying PCa metastasis are not fully understood. In this study, we discovered pronounced hypoxia in primary lesions of metastatic PCa(mPCa). The exosomes secreted by cancer-associated fibroblasts (CAFs) under hypoxic conditions significantly enhance PCa metastasis both in vitro and in vivo. Through miRNA sequencing and reverse transcription quantitative PCR (RT-qPCR), we found that hypoxia elevated miR-500a-3p levels in CAFs exosomes. Subsequent RT-qPCR, western blotting, and dual luciferase reporter assays identified F-box and WD repeat domain-containing 7(FBXW7) as a target of miR-500a-3p. In addition, immunohistochemistry revealed that FBXW7 expression decreased with the progression of PCa, while heat shock transcription factor 1(HSF1) expression increased. Introducing an FBXW7 plasmid into PCa cells reduced their metastatic potential and significantly lowered HSF1 expression. These findings suggest that CAFs exosomes drive PCa metastasis via the miR-500a-3p/FBXW7/HSF1 axis in a hypoxic microenvironment. Targeting either hypoxia or exosomal miR-500a-3p could be a promising strategy for PCa management.

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Fig. 1: Influence of CAF-CM on the progression of PCa cells under hypoxic microenvironment.
Fig. 2: Roles of CAF-derived exosomes in facilitating PCa progression within the hypoxic TME.
Fig. 3: Profiling distinctively expressed miRNAs in CAF hypoxic and normoxic exosomes.
Fig. 4: Exosomal miR-500a-3p: A Distinctive Indicator of Prostate Cancer Progression.
Fig. 5: FBXW7 was a target gene of miR-500a-3p.
Fig. 6: FBXW7 regulate PCa progression through suppressing HSF1 expression.
Fig. 7: Schematic illustration of the effect of hypoxic exosomes from CAFs on PCa progression.

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All data generated and analyzed during this study are available on request.

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Author notes

  1. These authors contributed equally: Zhanliang Liu, Zhemin Lin.

Authors and Affiliations

  1. Beijing Friendship Hospital, Capital Medical University, 100050, Beijing, China

    Zhanliang Liu, Mingxin Jiang, Tianyu Xiong & Y. N. Niu

  2. Beijing Shijitan Hospital, Capital Medical University, 100038, Beijing, China

    Zhemin Lin & Guangyi Zhu

  3. Cancer Hospital, Chinese Academy of Medical Science, 100021, Beijing, China

    Fang Cao

  4. Beijing Chaoyang Hospital, Capital Medical University, 100016, Beijing, China

    Yun Cui

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Contributions

ZL: formal analysis, investigation, validation, and writing- original draft. Zhemin Lin: formal analysis, visualization, data curation. MJ: and GZ: resources. TX: and FC: visualization. YN Niu and CY: supervision, funding acquisition, and writing – review & editing. This work was supported by the National Natural Science Foundation of China (No.82170783 and 82200859).

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Correspondence to Yun Cui or Y. N. Niu.

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Liu, Z., Lin, Z., Jiang, M. et al. Cancer-associated fibroblast exosomes promote prostate cancer metastasis through miR-500a-3p/FBXW7/HSF1 axis under hypoxic microenvironment. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00742-2

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