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Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis

Oncogene volume 34, pages 2690–2699 (2015)Cite this article

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Abstract

Tumor–stromal interaction is a dynamic process that promotes tumor growth and metastasis via cell–cell interaction and extracellular vesicles. Recent studies demonstrate that stromal fibroblast-derived molecular signatures can be used to predict disease progression and drug resistance. To identify the epigenetic role of stromal noncoding RNAs in tumor–stromal interactions in the tumor microenvironment, we performed microRNA profiling of patient cancer-associated prostate stromal fibroblasts isolated by laser capture dissection microscopy and in bone-associated stromal models. We found specific upregulation of miR-409-3p and miR-409-5p located within the embryonically and developmentally regulated DLK1-DIO3 (delta-like 1 homolog-deiodinase, iodothyronine 3) cluster on human chromosome 14. The findings in cell lines were further validated in human prostate cancer tissues. Strikingly, ectopic expression of miR-409 in normal prostate fibroblasts conferred a cancer-associated stroma-like phenotype and led to the release of miR-409 via extracellular vesicles to promote tumor induction and epithelial-to-mesenchymal transition in vitro and in vivo. miR-409 promoted tumorigenesis through repression of tumor suppressor genes such as Ras suppressor 1 and stromal antigen 2. Thus, stromal fibroblasts derived miR-409-induced tumorigenesis, epithelial-to-mesenchymal transition and stemness of the epithelial cancer cells in vivo. Therefore, miR-409 appears to be an attractive therapeutic target to block the vicious cycle of tumor–stromal interactions that plagues prostate cancer patients.

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Acknowledgements

This study was supported by a grant from P01-CA98912, DAMD-17-03-02-0033, RO1-CA122602 (LWKC) and TMU102-AE-B01, NSC102-2320-B-039-058, and MOHW103-TD-B-111-01 (S-YS). Dr Haga is funded by the TSRI Stem Cell fellowship. We thank Dr Ladan Fazli for providing the Gleason score tissue array. We also thank Dror Berel for helping with the statistical analysis.

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Author notes

  1. S Josson, M Gururajan and S Y Sung: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Uro-Oncology Research Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    S Josson, M Gururajan, P Hu, C Shao, H E Zhau, C Liu, J Lichterman, P Duan, E M Posadas & L W K Chung

  2. The Ph.D. program for Translational Medicine, Taipei Medical University, Taipei, Taiwan

    S Y Sung

  3. Biostatistics and Bioinformatics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Q Li & A Rogatko

  4. The Scripps Research Institute, Jupiter, FL, USA

    C L Haga

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Correspondence to L W K Chung.

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Josson, S., Gururajan, M., Sung, S. et al. Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene 34, 2690–2699 (2015). https://doi.org/10.1038/onc.2014.212

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