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Transcription factor p53-mediated activation of miR-519d-3p and downregulation of E2F1 attenuates prostate cancer growth and metastasis

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Abstract

Prostate cancer (PCa) is a commonly diagnosed malignancy in men. The transcription factor p53, a well-known cancer suppressor, has been extensively analyzed in the progression of many tumor types, but its involvement in PCa remains not fully understood. Hence, this study aims to explore the possible molecular mechanism underlying p53 in the growth and metastasis of PCa. Based on bioinformatics analysis findings of GEPIA and starBase databases, p53 was demonstrated to be involved in the development of PCa by transcriptionally activating microRNA-519d-3p (miR-519d-3p) expression to suppress the expression of E2F transcription factor 1 (E2F1) and CD147. In order to verify this finding, clinically-obtained PCa tumor tissues were enrolled and commercially-purchased PCa cell lines were used to detect the cell viability, cycle, and apoptosis, as well as invasion and migration by CCK-8, flow cytometry, and Transwell assays respectively. The results of clinical tissue experiments and in vitro cell experiments showed that miR-519d-3p and p53 were poorly-expressed in PCa tissues and cell lines, while E2F1 was highly-expressed. Overexpression of miR-519d-3p led to inhibited PCa cell proliferation, invasion and migration, and p53 overexpression was found to promote miR-519d-3p expression to suppress the malignant characteristics of PCa cells, while the additional E2F1 overexpression restored the malignant traits. Moreover, ChIP analysis and dual-luciferase reporter assay confirmed the interactions among p53, miR-519d-3p, and E2F1. Mechanistically, it was found that p53 transcriptionally activated miR-519d-3p to suppress E2F1 expression. Finally, the in vitro results were further validated by in vivo experiments, which showed that miR-519d-3p prevents tumorigenesis and lymph node metastasis of PCa in nude mice via negatively regulation of E2F1 and CD147. Taken together, the findings uncover that the transcription factor p53 could upregulate miR-519d-3p expression to directly suppress the expression of E2F1, thus inhibiting PCa growth and metastasis. It highlights a novel therapeutic strategy against PCa based on the p53/miR-519d-3p/E2F1 regulatory pathway.

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Fig. 1: Expression of miR-519d-3p in prostate cancer tissues and cells and its correlation with prognosis of prostate cancer patients.
Fig. 2: Effects of overexpression of miR-519d-3p on proliferation, invasion, and migration of PCa cells.
Fig. 3: Effect of p53 transcriptional activation of miR-519d-3p on E2F1 expression in prostate cancer.
Fig. 4: Effects of transcriptional activation of p53 by miR-519d-3p downregulates E2F1 expression on PCa cell proliferation, invasion, and migration.
Fig. 5: miR-519d-3p downregulates the expression of CD147 by inhibiting E2F1, thus alleviating the proliferation, invasion, and migration of PCa cells.
Fig. 6: miR-519d-3p downregulates the expression of CD147 by inhibiting E2F1, thus inhibiting PCa in vivo.
Fig. 7: Molecular networks.

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Funding

This study was supported by Free Exploration and Innovation Project of Xi’an Jiaotong University (Grant No.: XJJ2018138) and Natural Science Basic Research Project of Shaanxi Province (Grant No.: 2018JM7093).

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DZ, LX, and TC designed the study. X-JY and Q-DL were involved in data collection. DZ and LX performed the statistical analysis and preparation of figures. DZ and TC drafted and polished the paper. All authors read and approved the final manuscript.

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Correspondence to Tie Chong.

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Zhang, D., Yang, XJ., Luo, QD. et al. Transcription factor p53-mediated activation of miR-519d-3p and downregulation of E2F1 attenuates prostate cancer growth and metastasis. Cancer Gene Ther (2021). https://doi.org/10.1038/s41417-021-00405-6

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