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.

  • Original Article
  • Published:

miR-27a regulates endothelial differentiation of breast cancer stem like cells

Oncogene volume 33, pages 2629–2638 (2014)Cite this article

Subjects

Abstract

Recent studies suggested that cancer stem cells (CSCs) are capable of differentiating into endothelial cells and tumor endothelium may be derived from CSCs. But the mechanism remains unclear. We showed that vascular endothelial growth factor (VEGF) induced the expression of endothelial markers in breast cancer stem like cells (BCSLCs). In addition, the VEGF-treated BCSLCs formed capillary structure in matrigel and released vWF upon histamine treatment. The miR-27a expression was significantly increased in VEGF-treated BCSLCs. Antagonizing miR-27a by miR-27a anti-sense oligos (ASOs) in VEGF-treated BCSLCs led to decreased endothelial markers and function, while increasing miR-27a in BCSLCs resulted in enhanced endothelial properties. VEGF enhanced the transcription of miR-27a by increasing RUNX1 binding to miR-27a promoter. Increased miR-27a paralleled the reduced expression of ZBTB10, a known miR-27a target. Both expression of miR-27a and knockdown of ZBTB10 in BCSLCs promoted in vivo angiogenesis and tumor metastasis. Further, we demonstrated that VEGF-treated BCSLCs secreted more endogenous VEGF compared with undifferentiated BCSLCs. Thus, miR-27a promotes angiogenesis by mediating endothelial differentiation of BCSLCs and it may be a new target for anti-angiogenesis cancer therapy.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  2. de Castro Junior G, Puglisi F, de Azambuja E, El Saghir NS, Awada A . Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the "do ut des" paradigm). Crit Rev Oncol Hematol 2006; 59: 40–50.

    Article  Google Scholar 

  3. Jain RK . Barriers to drug delivery in solid tumors. Sci Am 1994; 271: 58–65.

    Article  CAS  Google Scholar 

  4. Jain RK . Determinants of tumor blood flow: a review. Cancer Res 1988; 48: 2641–2658.

    CAS  Google Scholar 

  5. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155: 739–752.

    Article  CAS  Google Scholar 

  6. Hendrix MJ, Seftor EA, Hess AR, Seftor RE . Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 2003; 3: 411–421.

    Article  CAS  Google Scholar 

  7. Dome B, Hendrix MJ, Paku S, Tovari J, Timar J . Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am J Pathol 2007; 170: 1–15.

    Article  CAS  Google Scholar 

  8. Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 2010; 468: 829–833.

    Article  CAS  Google Scholar 

  9. Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010; 468: 824–828.

    Article  CAS  Google Scholar 

  10. Shcherbata HR, Hatfield S, Ward EJ, Reynolds S, Fischer KA, Ruohola-Baker H . The MicroRNA pathway plays a regulatory role in stem cell division. Cell Cycle 2006; 5: 172–175.

    Article  CAS  Google Scholar 

  11. Leonardo TR, Schultheisz HL, Loring JF, Laurent LC . The functions of microRNAs in pluripotency and reprogramming. Nat Cell Biol 2012; 14: 1114–1121.

    Article  CAS  Google Scholar 

  12. Fang K, Qian F, Chen YQ . MicroRNAs as regulators in normal hematopoietic and leukemia stem cells: current concepts and clinical implications. Curr Mol Med 2012; 12: 536–546.

    Article  CAS  Google Scholar 

  13. Liu C, Tang DG . MicroRNA regulation of cancer stem cells. Cancer Res 2011; 71: 5950–5954.

    Article  CAS  Google Scholar 

  14. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109–1123.

    Article  CAS  Google Scholar 

  15. Mertens-Talcott SU, Chintharlapalli S, Li X, Safe S . The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 2007; 67: 11001–11011.

    Article  CAS  Google Scholar 

  16. Weigand M, Hantel P, Kreienberg R, Waltenberger J . Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis 2005; 8: 197–204.

    Article  CAS  Google Scholar 

  17. Tang W, Zhu J, Su S, Wu W, Liu Q, Su F et al. MiR-27 as a prognostic marker for breast cancer progression and patient survival. PLoS One 2012; 7: e51702.

    Article  CAS  Google Scholar 

  18. Bussolati B, Grange C, Sapino A, Camussi G . Endothelial cell differentiation of human breast tumour stem/progenitor cells. J Cell Mol Med 2009; 13: 309–319.

    Article  CAS  Google Scholar 

  19. Zhou Q, Gallagher R, Ufret-Vincenty R, Li X, Olson EN, Wang S . Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters. Proc Natl Acad Sci USA 2011; 108: 8287–8292.

    Article  CAS  Google Scholar 

  20. Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 2007; 130: 691–703.

    Article  CAS  Google Scholar 

  21. Stratman AN, Davis MJ, Davis GE . VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines. Blood 2011; 117: 3709–3719.

    Article  Google Scholar 

  22. Ben-Ami O, Pencovich N, Lotem J, Levanon D, Groner Y . A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis. Proc Natl Acad Sci USA 2009; 106: 238–243.

    Article  CAS  Google Scholar 

  23. Wang J, Zhao HP, Lin G, Xie CQ, Nie DS, Wang QR et al. In vitro hematopoietic differentiation of human embryonic stem cells induced by co-culture with human bone marrow stromal cells and low dose cytokines. Cell Biol Int 2005; 29: 654–661.

    Article  CAS  Google Scholar 

  24. Fukumura D, Jain RK . Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 2007; 101: 937–949.

    Article  CAS  Google Scholar 

  25. Fukumura D, Jain RK . Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 2007; 74: 72–84.

    Article  CAS  Google Scholar 

  26. Fukumura D, Duda DG, Munn LL, Jain RK . Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models. Microcirculation 2010; 17: 206–225.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the 973 Projects (2010CB912800, 2011CB504203) from the Ministry of Science and Technology of China, and grants from the Natural Science Foundation of China (81072178, 81272894, 81230060, 81261140373, 81071788), Ministry of Education of China (20120171110075), a grant for Development of Important New Drugs from the Ministry of Health of China (2011ZX09102-010-02), grants from Guangdong Natural Science Fundation for Distinguished Young Scholar (S20120011199) and Foundation for the Author of National Excellent Doctoral Dissertation of PR China (FANEDD, 81000-3149001).

Author information

Author notes

  1. W Tang, F Yu and H Yao: These authors contributed equally to this work.

Authors and Affiliations

  1. Breast Tumor Center, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, People’s Republic of China

    W Tang, F Yu, H Yao, L Lin, J Chen, E Song & Q Liu

  2. Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Medical Research Center, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou, People’s Republic of China

    X Cui & D Yin

  3. School of Life Sciences, Sun-Yat-Sen University, Guangzhou, People’s Republic of China

    Y Jiao

Authors
  1. W Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Q Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to E Song or Q Liu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tang, W., Yu, F., Yao, H. et al. miR-27a regulates endothelial differentiation of breast cancer stem like cells. Oncogene 33, 2629–2638 (2014). https://doi.org/10.1038/onc.2013.214

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.214

Keywords

This article is cited by

Search

Advanced search

Quick links