Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway

Subjects

Abstract

Bone metastasis is the most common complication responsible for most deaths in the advanced stages of prostate cancer (PCa). However, the exact mechanism of bone metastasis in PCa remains unelucidated. Herein, we explored the function and potential underlying mechanism of exosomal miR-375 in bone metastasis and tumor progression in PCa. This study revealed that miR-375 expression was markedly upregulated in advanced PCa with bone metastasis and metastatic PCa cell lines. Moreover, miR-375 showed high expression in PCa-derived exosomes and could be delivered to human mesenchymal stem cells (hMSCs) via exosomes. Mechanistically, miR-375 directly targeted DIP2C and upregulated the Wnt signaling pathway, thereby promoting osteoblastic differentiation in hMSCs. Furthermore, miR-375 promoted the proliferation, invasion, and migration of PCa cells in vitro and enhanced tumor progression and osteoblastic metastasis in vivo. Notably, the expression of miR-375, TCF-1, LEF-1, and β-catenin in was higher in PCa tissues with bone metastasis than in PCa tissues without bone metastasis and showed a continuous increase, whereas DIP2C, cyclin D1, and Axin2 showed an opposite expression pattern. In conclusion, our study suggests that cancer-derived exosomal miR-375 targets DIP2C, activates the Wnt signaling pathway, and promotes osteoblastic metastasis and PCa progression.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Cancer-derived miR-375 is transferred via exosomes to human mesenchymal stem cells.
Fig. 2: Cancer-secreted miR-375 promotes the osteoblastic differentiation of hMSCs.
Fig. 3: DIP2C is target of miR-375 to promote osteoblastic differentiation in hMSCs.
Fig. 4: Cancer-secreted miR-375 promotes osteoblastic differentiation of hMSCs through Wnt signaling.
Fig. 5: miR-375 enhances proliferation, migration, and invasion of PCa cells.
Fig. 6: miR-375 promotes progression and metastasis of PCa in vivo.
Fig. 7: Correlation of miR-375 with DIP2C and Wnt signaling pathway in human PCa tissues.
Fig. 8: The mechanism scheme of exosomal miR-375 promoting PCa progression and bone.

Data availability

All data included in this study are available upon request by contact with the corresponding author.

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  3. Beltran H, Beer TM, Carducci MA, de Bono J, Gleave M, Hussain M, et al. New therapies for castration-resistant prostate cancer: efficacy and safety. Eur Urol. 2011;60:279–90.

    Article  CAS  PubMed  Google Scholar 

  4. Suzman DL, Boikos SA, Carducci MA. Bone-targeting agents in prostate cancer. Cancer Metastasis Rev. 2014;33:619–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hashimoto K, Ochi H, Sunamura S, Kosaka N, Mabuchi Y, Fukuda T, et al. Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A. Proc Natl Acad Sci USA. 2018;115:2204–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dolloff NG, Shulby SS, Nelson AV, Stearns ME, Johannes GJ, Thomas JD, et al. Bone-metastatic potential of human prostate cancer cells correlates with Akt/PKB activation by alpha platelet-derived growth factor receptor. Oncogene. 2005;24:6848–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dai J, Kitagawa Y, Zhang J, Yao Z, Mizokami A, Cheng S, et al. Vascular endothelial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic protein. Cancer Res. 2004;64:994–9.

    Article  CAS  PubMed  Google Scholar 

  8. Yin JJ, Mohammad KS, Kakonen SM, Harris S, Wu-Wong JR, Wessale JL, et al. A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci USA. 2003;100:10954–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Farrugia AN, Atkins GJ, To LB, Pan B, Horvath N, Kostakis P, et al. Receptor activator of nuclear factor-kappaB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo. Cancer Res. 2003;63:5438–45.

    CAS  PubMed  Google Scholar 

  10. Boucharaba A, Serre CM, Gres S, Saulnier-Blache JS, Bordet JC, Guglielmi J, et al. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest. 2004;114:1714–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262:9412–20.

    Article  CAS  PubMed  Google Scholar 

  12. Soung YH, Ford S, Zhang V, Chung J. Exosomes in cancer diagnostics. Cancers. 2017;9:8.

  13. Ye Y, Li SL, Ma YY, Diao YJ, Yang L, Su MQ, et al. Exosomal miR-141-3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer. Oncotarget. 2017;8:94834–49.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hassan MQ, Maeda Y, Taipaleenmaki H, Zhang W, Jafferji M, Gordon JA, et al. miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells. J Biol Chem. 2012;287:42084–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Duan Y, Tan Z, Yang M, Li J, Liu C, Wang C, et al. PC-3-derived exosomes inhibit osteoclast differentiation by downregulating miR-214 and blocking NF-kappaB signaling pathway. Biomed Res Int. 2019;2019:8650846.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wu XG, Zhou CF, Zhang YM, Yan RM, Wei WF, Chen XJ, et al. Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma. Angiogenesis. 2019;22:397–410.

    Article  CAS  PubMed  Google Scholar 

  17. Li SL, An N, Liu B, Wang SY, Wang JJ, Ye Y. Exosomes from LNCaP cells promote osteoblast activity through miR-375 transfer. Oncol Lett. 2019;17:4463–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu H, Li PW, Yang WQ, Mi H, Pan JL, Huang YC, et al. Identification of non-invasive biomarkers for chronic atrophic gastritis from serum exosomal microRNAs. BMC Cancer. 2019;19:129.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Che Y, Shi X, Shi Y, Jiang X, Ai Q, Shi Y, et al. Exosomes derived from miR-143-overexpressing MSCs inhibit cell migration and invasion in human prostate cancer by downregulating TFF3. Mol Ther Nucleic Acids. 2019;18:232–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang XF, Zhang YK, Yu ZS, Zhou JL. The role of the serum RANKL/OPG ratio in the healing of intertrochanteric fractures in elderly patients. Mol Med Rep. 2013;7:1169–72.

    Article  CAS  PubMed  Google Scholar 

  21. Yu L, Sui B, Fan W, Lei L, Zhou L, Yang L, et al. Exosomes derived from osteogenic tumor activate osteoclast differentiation and concurrently inhibit osteogenesis by transferring COL1A1-targeting miRNA-92a-1-5p. J Extracell Vesicles. 2021;10:e12056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yoneda T, Williams PJ, Hiraga T, Niewolna M, Nishimura R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Min Res. 2001;16:1486–95.

    Article  CAS  Google Scholar 

  23. Murillo-Garzon V, Kypta R. WNT signalling in prostate cancer. Nat Rev Urol. 2017;14:683–96.

    Article  CAS  PubMed  Google Scholar 

  24. Pickl JM, Tichy D, Kuryshev VY, Tolstov Y, Falkenstein M, Schuler J, et al. Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression. Oncotarget. 2016;7:59589–603.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gan TQ, Chen WJ, Qin H, Huang SN, Yang LH, Fang YY, et al. Clinical value and prospective pathway signaling of microRNA-375 in lung adenocarcinoma: A study based on the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and bioinformatics analysis. Med Sci Monit. 2017;23:2453–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ye XM, Zhu HY, Bai WD, Wang T, Wang L, Chen Y, et al. Epigenetic silencing of miR-375 induces trastuzumab resistance in HER2-positive breast cancer by targeting IGF1R. BMC Cancer. 2014;14:134.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T, et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010;70:2339–49.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Lieberman R, Pan J, Zhang Q, Du M, Zhang P, et al. miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1. Mol Cancer. 2016;15:70.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Selth LA, Das R, Townley SL, Coutinho I, Hanson AR, Centenera MM, et al. A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer. Oncogene. 2017;36:24–34.

    Article  CAS  PubMed  Google Scholar 

  30. Choi N, Park J, Lee JS, Yoe J, Park GY, Kim E, et al. miR-93/miR-106b/miR-375-CIC-CRABP1: A novel regulatory axis in prostate cancer progression. Oncotarget. 2015;6:23533–47.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Costa-Pinheiro P, Ramalho-Carvalho J, Vieira FQ, Torres-Ferreira J, Oliveira J, Goncalves CS, et al. MicroRNA-375 plays a dual role in prostate carcinogenesis. Clin Epigenetics. 2015;7:42.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Foj L, Ferrer F, Serra M, Arevalo A, Gavagnach M, Gimenez N, et al. Exosomal and non-exosomal urinary miRNAs in. Prostate Cancer Detection Prognosis Prostate. 2017;77:573–83.

    CAS  PubMed  Google Scholar 

  33. Gao Y, Guo Y, Wang Z, Dai Z, Xu Y, Zhang W, et al. Analysis of circulating miRNAs 21 and 375 as potential biomarkers for early diagnosis of prostate cancer. Neoplasma. 2016;63:623–8.

    Article  CAS  PubMed  Google Scholar 

  34. Wach S, Al-Janabi O, Weigelt K, Fischer K, Greither T, Marcou M, et al. The combined serum levels of miR-375 and urokinase plasminogen activator receptor are suggested as diagnostic and prognostic biomarkers in prostate cancer. Int J Cancer. 2015;137:1406–16.

    Article  CAS  PubMed  Google Scholar 

  35. Hart M, Nolte E, Wach S, Szczyrba J, Taubert H, Rau TT, et al. Comparative microRNA profiling of prostate carcinomas with increasing tumor stage by deep sequencing. Mol Cancer Res. 2014;12:250–63.

    Article  CAS  PubMed  Google Scholar 

  36. Cheng HH, Mitchell PS, Kroh EM, Dowell AE, Chery L, Siddiqui J, et al. Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia. PLoS One. 2013;8:e69239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hlavna M, Raudenska M, Hudcova K, Gumulec J, Sztalmachova M, Tanhauserova V, et al. MicroRNAs and zinc metabolism-related gene expression in prostate cancer cell lines treated with zinc(II) ions. Int J Oncol. 2012;41:2237–44.

    Article  CAS  PubMed  Google Scholar 

  38. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: Diagnostics, monitoring, and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4:143–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McDonald AC, Vira M, Shen J, Sanda M, Raman JD, Liao J, et al. Circulating microRNAs in plasma as potential biomarkers for the early detection of prostate cancer. Prostate. 2018;78:411–8.

    Article  CAS  PubMed  Google Scholar 

  40. Kachakova D, Mitkova A, Popov E, Popov I, Vlahova A, Dikov T, et al. Combinations of serum prostate-specific antigen and plasma expression levels of let-7c, miR-30c, miR-141, and miR-375 as potential better diagnostic biomarkers for prostate cancer. DNA Cell Biol. 2015;34:189–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Han L, Lam EW, Sun Y. Extracellular vesicles in the tumor microenvironment: Old stories, but new tales. Mol Cancer. 2019;18:59.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jiao X, Wood LD, Lindman M, Jones S, Buckhaults P, Polyak K, et al. Somatic mutations in the Notch, NF-KB, PIK3CA, and Hedgehog pathways in human breast cancers. Genes Chromosomes Cancer. 2012;51:480–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li J, Ping JL, Ma B, Chen YR, Li LQ. DIP2C expression in breast cancer and its clinical significance. Pathol Res Pr. 2017;213:1394–9.

    Article  CAS  Google Scholar 

  44. Larsson C, Ali MA, Pandzic T, Lindroth AM, He L, Sjoblom T. Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition. BMC Cancer. 2017;17:487.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The work was funded by the President Foundation of Nanfang Hospital, Southern Medical University [grant number: 2020B025].

Author information

Authors and Affiliations

Authors

Contributions

HSH: Conceptualization; LY and YCM: Methodology; HSH: Validation; LY, YCM, CSS, and LWH: Investigation; YCM and CSS: Resources; YCM: Writing - original draft; CSS and LJY: Writing - review & editing; CSS and LJY: Visualization; LY and LJY: Supervision; HJL: Project administration; HJL and HSH: Funding acquisition.

Corresponding authors

Correspondence to Shuhua He or Jialiang Hui.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

All mouse experiments were approved by the Nanfang Hospital Animal Ethics Committee (approval no. NFYY-2019-1227).

Consent for publication

This article is original, has not already been published in a journal, and is not currently under consideration by another journal.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, Y., Yang, C., Chen, S. et al. Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00563-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41417-022-00563-1

Search

Quick links