Skip to main content

Advertisement

SpringerLink
Log in

MiR-944 functions as a novel oncogene and regulates the chemoresistance in breast cancer

  • Original Article
  • Published:
Tumor Biology

Abstract

MircroRNAs are emerging as critical regulators in carcinogenesis and chemoresistance in multiple cancer types. In this study, we observed that the miR-944 level was upregulated in breast cancer patients’ serum and tumor tissues, suggesting that miR-944 is a tumor promoter in breast cancer. To investigate the role of miR-944, we performed gain- and loss-of-function experiments in vitro. We then demonstrated that miR-944 promotes cell proliferation and tumor metastasis in breast cancer cell lines. Furthermore, we indicated that miR-944 is associated with cisplatin resistance by targeting BNIP3. Knockdown of the miR-944 by specific inhibitors significantly increased the cytotoxicity of cisplatin in cisplatin-resistant MCF-7 cells (MCF-7/R). Importantly, we found that the sensitization of miR-944 inhibitors to cisplatin cytotoxicity was abolished by BNIP3 siRNA which decreased the expression of BNIP3 gene. Finally, we demonstrated that miR-944 inhibitors promoted the loss of mitochondrial membrane potential (MMP) caused by cisplatin in MCF-7/R cells, resulting in the release of mitochondria-derived apoptogenic proteins into cytoplasm, and then, the caspase-3 was activated. In summary, our study showed that miR-944 functions as a novel oncogene and regulates the cisplatin resistance in breast cancer. The miR-944-BNIP3-MMP-caspase-3 pathway might be a novel target for the chemotherapy of breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  2. Jerusalem G, Rorive A, Collignon J. Chemotherapy options for patients suffering from heavily pretreated metastatic breast cancer. Future Oncol. 2015;11:1775–89.

    Article  CAS  PubMed  Google Scholar 

  3. Yao YS, Qiu WS, Yao RY, Zhang Q, Zhuang LK, Zhou F, et al. miR-141 confers docetaxel chemoresistance of breast cancer cells via regulation of EIF4E expression. Oncol Rep. 2015;33:2504–12.

    CAS  PubMed  Google Scholar 

  4. Arslan C, Ozdemir E, Dogan E, Ozisik Y, Altundag K. Secondary hematological malignancies after treatment of non-metastatic breast cancer. J BUON. 2011;16:744–50.

    CAS  PubMed  Google Scholar 

  5. Mohell N, Alfredsson J, Fransson Å, Uustalu M, Byström S, Gullbo J, et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis. 2015;6, e1794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gao JH, Chen FH, Wang L, Wei H, Meng SL. YM155 inhibits tumor growth and enhances chemosensitivity to cisplatin in osteosarcoma. Eur Rev Med Pharmacol Sci. 2015;19:2062–9.

    PubMed  Google Scholar 

  7. Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113:673–6.

    Article  CAS  PubMed  Google Scholar 

  8. Nair N, Gongora E. MicroRNAs as therapeutic targets in cardiomyopathies: myth or reality? Biomol Concepts. 2014;5:439–48.

    Article  CAS  PubMed  Google Scholar 

  9. Wolfson B, Eades G, Zhou Q. Roles of microRNA-140 in stem cell-associated early stage breast cancer. World J Stem Cells. 2014;6:591–7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mo ZH, Wu XD, Li S, Fei BY, Zhang B. Expression and Clinical Significance of MicroRNA-376a in Colorectal Cancer. Asian Pac J Cancer Prev. 2014;15:9523–7.

    Article  PubMed  Google Scholar 

  11. Toraih EA, Mohammed EA, Farrag S, Ramsis N, Hosny S. Pilot Study of Serum MicroRNA-21 as a Diagnostic and Prognostic Biomarker in Egyptian Breast Cancer Patients. Mol Diagn Ther. 2015;19:179–90.

    Article  CAS  PubMed  Google Scholar 

  12. Kaboli PJ, Rahmat A, Ismail P, Ling KH. MicroRNA-based therapy and breast cancer: A comprehensive review of novel therapeutic strategies from diagnosis to treatment. Pharmacol Res. 2015;97:104–21.

    Article  CAS  PubMed  Google Scholar 

  13. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  14. Chen C, Ridzon DA, Lee DH, et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005;33, e179.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wang J, Tian X, Han R, Zhang X, Wang X, Shen H, et al. Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene. 2014;33:1181–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gu JW, Bailey AP, Sartin A, Makey I, Brady AL. Ethanol stimulates tumor progression and expression of vascular endothelial growth factor in chick embryos. Cancer. 2005;103:422–31.

    Article  CAS  PubMed  Google Scholar 

  17. Chen H, Zhu G, Li Y, Padia RN, Dong Z, Pan ZK, et al. Extracellular signal–regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res. 2009;69:9228–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Prathapan A, Vineetha VP, Raghu KG. Protective effect of Boerhaavia diffusa L. against mitochondrial dysfunction in angiotensin II induced hypertrophy in H9c2 cardiomyoblast cells. PLoS One. 2014;9, e96220.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ray R, Chen G, Vande Velde C, et al. BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3(BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem. 2000;275:1439–48.

    Article  CAS  PubMed  Google Scholar 

  20. Kaza N, Kohli L, Roth KA, et al. BNIP3 regulates AT101 [(−)-gossypol] induced death in malignant peripheral nerve sheath tumor cells. PLoS One. 2014;9, e96733.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Witten D, Tibshirani R, Gu SG, et al. Ultra-high throughput sequencing-based small RNA discov ery and discrete statistical biomarker analysis in a collection of cervical tumours and matched controls. BMC Biol. 2010;8:58.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Christensen LL, Tobiasen H, Holm A, et al. MiRNA-362-3p induces cell cycle arrest through targeting of E2F1, USF2 and PTPN1 and is associated with recurrence of colorectal cancer. Int J Cancer. 2013;133:67–78.

    Article  PubMed  Google Scholar 

  23. Nordentoft I, Birkenkamp-Demtroder K, Agerbaek M, et al. miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer. BMC Med Genomics. 2012;5:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yin W, Nie Y, Zhang Z, Xie L, He X. miR-193b acts as a cisplatin sensitizer via the caspase-3-dependent pathway in HCC chemotherapy. Oncol Rep. 2015;34:368–74.

    CAS  PubMed  Google Scholar 

  25. Weiner-Gorzel K, Dempsey E, Milewska M, McGoldrick A, Toh V, Walsh A, et al. Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells. Cancer Med. 2015;4:745–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jiang C, Long J, Liu B, Xie X, Kuang M. Mcl-1 Is a Novel Target of miR-26b That Is Associated with the Apoptosis Induced by TRAIL in HCC Cells. Biomed Res Int. 2015;2015:572738.

    PubMed  PubMed Central  Google Scholar 

  27. Ray R, Chen G, Vande Velde C, et al. BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3(BH3) domain at both mitochondrial and nonmitochondrial sites. J Biol Chem. 2000;275:1439–48.

    Article  CAS  PubMed  Google Scholar 

  28. Gustafsson AB. Bnip3 as a dual regulator of mitochondrial turnover and cell death in the myocardium. Pediatr Cardiol. 2011;32:267–74.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rikka S, Quinsay MN, Thomas RL, Kubli DA, Zhang X, Murphy AN, et al. Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover. Cell Death Differ. 2011;18:721–31.

    Article  CAS  PubMed  Google Scholar 

  30. Erkan M, Kleeff J, Esposito I, Giese T, Ketterer K, Büchler MW, et al. Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene. 2005;24:4421–32.

    Article  CAS  PubMed  Google Scholar 

  31. Zu Y, Yang Z, Tang S, Han Y, Ma J. Effects of p-glycoprotein and its inhibitors on apoptosis in k562 cells. Molecules. 2014;19:13061–75.

    Article  PubMed  Google Scholar 

  32. Zhao JX, Liu H, Lv J, Yang XJ. Wortmannin enhances cisplatin-induced apoptosis in human ovarian cancer cells in vitro. Eur Rev Med Pharmacol Sci. 2014;18:2428–34.

    PubMed  Google Scholar 

  33. Tian HY, Li ZX, Li HY, Wang HJ, Zhu XW, Dou ZH. Effects of 14 single herbs on the induction of caspase-3 in tumor cells: a brief review. Chin J Integr Med. 2013;19:636–40.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Thanks are due to Medical and health research projects in Zhejiang Province (grant no: 2014KYA094) and The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education for supporting this study

Compliance with ethical standards

The study was approved by Ethic Committee of The Second Affiliated Hospital, School of medicine, Zhejiang University.

Author contributions

KJ designed the study. KJ and HH wrote the manuscript. HH and WT performed out the immunohistochemistry and the related statistical analysis. HH, HC, and KJ carried out the cell culture and transfection, Western blot, RT-PCR, and flow Ccytometry. All authors approved the final version of the manuscript.

Conflicts of interest

The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, The Second Affiliated Hospital, School of medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China

    Haifei He, Wei Tian & Hailong Chen

  2. Cancer Institute (The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China

    Wei Tian & Hailong Chen

  3. Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Gucui Road 234#, Xihu District, Hangzhou city province, Zhejiang, 310012, China

    Kai Jiang

Authors
  1. Haifei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hailong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kai Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kai Jiang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, H., Tian, W., Chen, H. et al. MiR-944 functions as a novel oncogene and regulates the chemoresistance in breast cancer. Tumor Biol. 37, 1599–1607 (2016). https://doi.org/10.1007/s13277-015-3844-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3844-x

Keywords

Search

Navigation