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Cellular and Molecular Biology

miR-199b-5p-DDR1-ERK signalling axis suppresses prostate cancer metastasis via inhibiting epithelial-mesenchymal transition

British Journal of Cancer volume 124, pages 982–994 (2021)Cite this article

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A Correction to this article was published on 13 January 2021

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Abstract

Background

The investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.

Methods

The current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.

Results

We demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3’-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.

Conclusions

Our study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

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Fig. 1: miR-199b-5p expression is remarkably downregulated in metastatic PCa tissue samples and cells, but independent of AR expression.
Fig. 2: miR-199b-5p inhibits tumour growth and metastasis in vivo.
Fig. 3: DDR1 is a functional target of miR-199b-5p in PCa.
Fig. 4: DDR1 affects ERK signalling pathway in PCa.
Fig. 5: DDR1 induces EMT phenotype in PCa.

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Acknowledgements

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Author notes

  1. These authors contributed equally: Zhigang Zhao, Shankun Zhao, Lianmin Luo, Qian Xiang

Authors and Affiliations

  1. Department of Urology & Andrology, The First Affiliated Hospital of Guangzhou Medical University; Guangdong Provincial Key Laboratory of Urology, 510230, Guangzhou, China

    Zhigang Zhao, Lianmin Luo, Qian Xiang, Zhiguo Zhu, Jiamin Wang, Yangzhou Liu & Jintai Luo

  2. Department of Urology, Zhejiang Taizhou Central Hospital (Affiliated Hospital of Taizhou University), 318000, Taizhou, China

    Shankun Zhao

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Contributions

S.Z., L.L. and Q.X. conducted most of in vitro and in vivo experiments, generated site-directed mutagenesis clones and performed tumour studies in mice. J.W. performed the immunoblotting analysis and captured images of immunohistochemistry. S.Z. and Y.L. conducted in vivo imaging and necropsy of mice. Z. Zhu performed bioinformatics analyses using online tools. J.L. coordinated acquisition of human PCa patient tissues, pathologically reviewed these patient specimens and scored them based on the staining intensity. Z. Zhao conceived, designed and supervised the work. Z. Zhao and S.Z. critically analysed data, prepared figures and tables and wrote the paper. All of the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Zhigang Zhao.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University, and the written informed consent was obtained from all patients before participating in the study. Human specimens were handled and made anonymous in adherence to the ethical and legal standards. All procedures related to the animal experiments in this study were carried out in accordance with a mouse protocol, which was reviewed and approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Guangzhou Medical University.

Consent for publication

Not applicable.

Data availability

Data pertaining to this study are included in the manuscript. TargetScan, miRDB, miRWalk, miRTarBase, The Cancer Genome Atlas database (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and the Gene Expression Omnibus (GEO) datasets used and/or analysed in this work are publicly available from http://www.targetscan.org/, http://mirdb.org/, http://zmf.umm.uni-heidelberg.de/, http://mirtarbase.mbc.nctu.edu/, https://tcgadata.nci.nih.gov/tcga/, http://gepia.cancer-pku.cn/ and http://www.ncbi.nlm.nih.gov/geo/, respectively. Other data that support the findings of this study are available from the corresponding author upon request.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the grants from National Natural Science Foundation of China (81572537 to Z. Zhao), The Key Program of Natural Science Foundation of Guangdong Province (2015A030311007 to Z. Zhao), Science and Technology Program of Guangzhou (201607010376 to Z. Zhao) and The Major Program of Department of Guangdong Education (2017KZDXM067 to Z. Zhao).

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Zhao, Z., Zhao, S., Luo, L. et al. miR-199b-5p-DDR1-ERK signalling axis suppresses prostate cancer metastasis via inhibiting epithelial-mesenchymal transition. Br J Cancer 124, 982–994 (2021). https://doi.org/10.1038/s41416-020-01187-8

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