Abstract
For human prostate cancer, the chromosome 8p21 locus, which contains NKX3.1 and the microRNA (miR)-3622 family (miR-3622a/b), is a frequently deleted region. Thus, miR-3622 is proposed as a suppressor for prostate cancer, but its role remains debatable. In the present study, we found that expression of miR-3622a was lower, whereas expression of miR-3622b-3p was higher in human prostate cancer tissues than in normal prostate tissues. miR-3622a-3p inhibited cell migration and invasion of human prostate cancer cells, whereas miR-3622b-3p facilitated cell proliferation, migration, and invasion. To address the opposing roles of miR-3622 family members in various human prostate cancer cell lines, we knocked out (KO) endogenous miR-3622, including both miR-3622a/b. Our results showed that miR-3622 KO reduced cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Functional analyses revealed that miR-3622 regulated the p53-downstream gene network, including AIFM2, c-MYC, and p21, to control apoptosis and the cell cycle. Furthermore, using CRISPR interference, miRNA/mRNA immunoprecipitation assays, and dual-luciferase assays, we established that AIFM2, a direct target of miR-3622b-3p, is responsible for miR-3622 KO-induced apoptosis. We identified an miR-3622-AIFM2 axis that contributes to oncogenic function during tumor progression. In addition, miR-3622 KO inhibited the epithelial–mesenchymal transition involved in prostate cancer metastasis via upregulation of vimentin. The results show that miR-3622b-3p is upregulated in human prostate cancers and has an oncogenic function in tumor progression and metastasis via repression of p53 signaling, especially through an miR-3622-AIFM2 axis. In contrast, for human prostate cancer, deletion of the miR-3622 locus at 8p21 reduced the oncogenic effects on tumor progression and metastasis.
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Acknowledgements
We thank Dr. Donald Hill for editorial assistance in preparing this paper. This work was supported by grants from the National Cancer Institute (CA118948 for LW), the Department of Defense (W81XWH-21-1-0100 for LW and W81XWH-15-1-0323 and W81XWH-20-1-0426 for RL) and the Mike Slive Foundation for Prostate Cancer Research (RL). Results are based, in part, upon data generated by TargetScan (http://www.targetscan.org/), the UALCAN portal (http://ualcan.path.uab.edu/), and the cBioPortal (http://www.cbioportal.org).
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Conception, design, and financial support: RL, LW. Development of methodology:YZ, JZ, LW, and RL. Acquisition of data (bench/animal works, acquired data, etc.): YZ, ZX, WW, ZL, CZ, ML, and FH. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): YZ, SB, RL, and LW. Writing, review, and/or revision of the paper: YZ, RL, and LW. Pathology analysis: YZ, SW, and LW. Study supervision: RL, LW.
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Zhang, Y., Xu, Z., Wen, W. et al. The microRNA-3622 family at the 8p21 locus exerts oncogenic effects by regulating the p53-downstream gene network in prostate cancer progression. Oncogene 41, 3186–3196 (2022). https://doi.org/10.1038/s41388-022-02289-8
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DOI: https://doi.org/10.1038/s41388-022-02289-8
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