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.

  • Letter
  • Published:

The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44

Nature Medicine volume 17, pages 211–215 (2011)Cite this article

Subjects

Abstract

Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis1. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs2,3,4,5, and dysregulation of miRNAs has been implicated in tumorigenesis6. CSCs in many tumors—including cancers of the breast7, pancreas8, head and neck9, colon10,11, small intestine12, liver13, stomach14, bladder15 and ovary16—have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic17 and tumor-initiating and metastatic18,19 capacities are enriched in the CD44+ cell population, but whether miRNAs regulate CD44+ prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 _target20,21,22,23,24, was underexpressed in CD44+ prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44+ prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44− prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional _target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44+ prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Underexpression and tumor-inhibitory effects of miR-34a.
Figure 2: miR-34a inhibits prostate CSC properties.
Figure 3: Therapeutic effects of miR-34a.
Figure 4: CD44 is a direct and functional _target of miR-34a.

Similar content being viewed by others

References

  1. Visvader, J.E. & Lindeman, G.J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755–768 (2008).

    Article  CAS  Google Scholar 

  2. Croce, C.M. & Calin, G.A. miRNAs, cancer, and stem cell division. Cell 122, 6–7 (2005).

    Article  CAS  Google Scholar 

  3. Melton, C., Judson, R.L. & Blelloch, R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463, 621–626 (2010).

    Article  CAS  Google Scholar 

  4. Yu, F. et al. let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).

    Article  CAS  Google Scholar 

  5. Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).

    Article  CAS  Google Scholar 

  6. Esquela-Kerscher, A. & Slack, F.J. Oncomirs—microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259–269 (2006).

    Article  CAS  Google Scholar 

  7. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  Google Scholar 

  8. Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).

    Article  CAS  Google Scholar 

  9. Prince, M.E. et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl. Acad. Sci. USA 104, 973–978 (2007).

    Article  CAS  Google Scholar 

  10. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 104, 10158–10163 (2007).

    Article  CAS  Google Scholar 

  11. Du, L. et al. CD44 is of functional importance for colorectal cancer stem cells. Clin. Cancer Res. 14, 6751–6760 (2008).

    Article  CAS  Google Scholar 

  12. Zeilstra, J. et al. Deletion of the WNT _target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 68, 3655–3661 (2008).

    Article  CAS  Google Scholar 

  13. Yang, Z.F. et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13, 153–166 (2008).

    Article  CAS  Google Scholar 

  14. Takaishi, S. et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27, 1006–1020 (2009).

    Article  CAS  Google Scholar 

  15. Chan, K.S. et al. Identification, molecular characterization, clinical prognosis, and therapeutic _targeting of human bladder tumor-initiating cells. Proc. Natl. Acad. Sci. USA 106, 14016–14021 (2009).

    Article  CAS  Google Scholar 

  16. Zhang, S. et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 68, 4311–4320 (2008).

    Article  CAS  Google Scholar 

  17. Collins, A.T., Berry, P.A., Hyde, C., Stower, M.J. & Maitland, N.J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).

    Article  CAS  Google Scholar 

  18. Patrawala, L. et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25, 1696–1708 (2006).

    Article  CAS  Google Scholar 

  19. Patrawala, L., Calhoun-Davis, T., Schneider-Broussard, R. & Tang, D.G. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+α2β1+ cell population is enriched in tumor-initiating cells. Cancer Res. 67, 6796–6805 (2007).

    Article  CAS  Google Scholar 

  20. He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007).

    Article  CAS  Google Scholar 

  21. Raver-Shapira, N. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26, 731–743 (2007).

    Article  CAS  Google Scholar 

  22. Chang, T.C. et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26, 745–752 (2007).

    Article  CAS  Google Scholar 

  23. Bommer, G.T. et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr. Biol. 17, 1298–1307 (2007).

    Article  CAS  Google Scholar 

  24. Tarasov, V. et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 _target that induces apoptosis and G1-arrest. Cell Cycle 6, 1586–1593 (2007).

    Article  CAS  Google Scholar 

  25. Johnson, C.D. et al. The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 67, 7713–7722 (2007).

    Article  CAS  Google Scholar 

  26. Wiggins, J.F. et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 70, 5923–5930 (2010).

    Article  CAS  Google Scholar 

  27. Jeter, C.R. et al. Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells 27, 993–1005 (2009).

    Article  CAS  Google Scholar 

  28. Patrawala, L. et al. Side population (SP) is enriched in tumorigenic, stem-like cancer cells whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res. 65, 6207–6219 (2005).

    Article  CAS  Google Scholar 

  29. Bhatia, B. et al. Critical and distinct roles of p16 and telomerase in regulating the proliferative lifespan of normal human prostate epithelial progenitor cells. J. Biol. Chem. 283, 27957–27972 (2008).

    Article  CAS  Google Scholar 

  30. Li, H.W. et al. Methodologies in assaying prostate cancer stem cells. Methods Mol. Biol. 568, 85–138 (2009).

    Article  CAS  Google Scholar 

  31. Hermeking, H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 17, 193–199 (2010).

    Article  CAS  Google Scholar 

  32. Li, H., Chen, X., Calhoun-Davis, T., Claypool, K. & Tang, D.G. PC3 Human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res. 68, 1820–1825 (2008).

    Article  CAS  Google Scholar 

  33. Dontu, G. et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17, 1253–1270 (2003).

    Article  CAS  Google Scholar 

  34. Yamakuchi, M., Ferlito, M. & Lowenstein, C.J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl. Acad. Sci. USA 105, 13421–13426 (2008).

    Article  CAS  Google Scholar 

  35. Li, Y. et al. MicroRNA-34a inhibits glioblastoma growth by _targeting multiple oncogenes. Cancer Res. 69, 7569–7576 (2009).

    Article  CAS  Google Scholar 

  36. Miranda, K.C. et al. A pattern-based method for the identification of microRNA-_target sites and their corresponding RNA/RNA complexes. Cell 126, 1203–1217 (2006).

    Article  CAS  Google Scholar 

  37. Godar, S. et al. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62–73 (2008).

    Article  CAS  Google Scholar 

  38. Jin, L., Hope, K.J., Zhai, Q., Smadja-Joffe, F. & Dick, J.E. _targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 12, 1167–1174 (2006).

    Article  Google Scholar 

  39. Ji, Q. et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS ONE 4, e6816 (2009).

    Article  Google Scholar 

Download references

Acknowledgements

We thank K. Claypool and P. Whitney for FACS, the Histology Core for help with immunohistochemistry, K. Lin for statistical analysis, G. Calin for critically reading the manuscript and other members of the Tang lab for support and discussions. We also thank G. Hannon (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA) for the MSCV-PIG vector. This work was supported in part by grants from the US National Institutes of Health (R01-AG023374, R01-ES015888, R21-ES015893, R21-CA150009), the US Department of Defense (W81XWH-07-1-0616, W81XWH-08-1-0472) and Elsa Pardee Foundation (D.G.T.) and by two M.D. Anderson Cancer Center grants (CCSG-5 P30 CA016672-34 and ES007784). C. Liu and H. Li were supported in part by predoctoral fellowships from the US Department of Defense.

Author information

Authors and Affiliations

  1. Department of Molecular Carcinogenesis, the University of Texas M.D. Anderson Cancer Center, Science Park, Smithville, Texas, USA

    Can Liu, Bigang Liu, Xin Chen, Tammy Calhoun-Davis, Hangwen Li, Hong Yan, Collene Jeter, Sofia Honorio & Dean G Tang

  2. Program in Molecular Carcinogenesis, The University of Texas Graduate School of Biomedical Sciences (GSBS), Houston, Texas, USA

    Can Liu, Xin Chen, Lubna Patrawala & Dean G Tang

  3. Mirna Therapeutics, Inc., Austin, Texas, USA

    Kevin Kelnar, Jason F Wiggins, Andreas G Bader & David Brown

  4. The Hospital at Westlake, Austin, Texas, USA

    Randy Fagin

Authors
  1. Can Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin Kelnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bigang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tammy Calhoun-Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hangwen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lubna Patrawala
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Collene Jeter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sofia Honorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jason F Wiggins
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andreas G Bader
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Randy Fagin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Dean G Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.L., K.K., B.L., X.C. and L.P. designed and performed the experiments with help from C.J., T.C.-D., H.L., S.H., H.Y., J.F.W. and A.G.B., R.F. provided all HPCa samples. C.L. and D.G.T. prepared the manuscript. D.G.T., with help from D.B., designed the experiments and supervised the whole project. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Dean G Tang.

Ethics declarations

Competing interests

K.K, J.F.W, A.G.B. and D.B are employees of Mirna Therapeutics, Inc., which develops miRNA-based therapeutics.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Methods, Supplementary Figures 1–15 and Supplementary Tables 1 and 2 (PDF 2176 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, C., Kelnar, K., Liu, B. et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17, 211–215 (2011). https://doi.org/10.1038/nm.2284

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2284

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer
  NODES
INTERN 1
Project 1
twitter 1