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Tumor Biology

, Volume 37, Issue 5, pp 6837–6845 | Cite as

miR-27a regulates the sensitivity of breast cancer cells to cisplatin treatment via BAK-SMAC/DIABLO-XIAP axis

  • Sumei Zhou
  • Qidi Huang
  • Shurong Zheng
  • Kuailu Lin
  • Jie You
  • Xiaohua Zhang
Original Article

Abstract

MicroRNA-27a (miR-27a) has been reported to be an onco-microRNA in multiple cancers promoting tumor growth and metastasis, but the role of miR-27a in regulating the cancer sensitivity to chemotherapy remains unknown. In this study, upregulation of miR-27a was validated by real-time PCR analysis in breast cancer (BC) cell lines and samples of BC patients. A negative correlation between miR-27a and bak was also observed in normal breast epithelial cell line MCF-10A and BC cell lines, suggesting that the bak is the potential target of miR-27a. miR-27a could modulate the growth and metastasis of BC cells. More importantly, we found that knockdown of miR-27a by the specific inhibitors significantly increased the sensitivity of T-47D cells to cisplatin (CDDP) treatment. After further investigation, we indicated that the knockdown of miR-27a promoted the apoptosis via mitochondrial pathway in T-47D cells treated with CDDP, depending on the BAK-second mitochondria-derived activator of caspase/direct IAP binding protein with low pI (SMAC/DIABLO)-X-linked inhibitor of apoptosis (XIAP) axis. Interestingly, we found that the sensitivity of T-47D cells to some other chemotherapeutic agents (5-fluorouracil, doxorubicin, and tumor necrosis factor-related apoptosis-inducing ligand) was also regulated by miR-27a. These findings improve our understanding of the role of miR-27a in breast cancer and might provide a novel strategy for cancer therapy.

Keywords

Breast cancer Cisplatin miR-27a BAK SMAC/DIABLO XIAP 

Notes

Acknowledgments

Thanks are due to Central Laboratory of The First Affiliated Hospital of Wenzhou Medical University for supporting this study

Author contributions

XZ designed the study. SZ and XZ wrote the manuscript. SZ, QH, and KL measured the sensitivity of tumor cells and the related statistical analysis. SZ and JY carried out the cell culture and transfection, Western blot, RT-PCR, and flow cytometry. All authors approved the final version of the manuscript.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Zheng L, Zhang X, Yang F, Zhu J, Zhou P, Yu F, et al. Regulation of the P2X7R by microRNA-216b in human breast cancer. Biochem Biophys Res Commun. 2014;452:197–204.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z, Jenal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Sapio L, Sorvillo L, Illiano M, Chiosi E, Spina A, Naviglio S. Inorganic phosphate prevents Erk1/2 and Stat3 activation and improves sensitivity to doxorubicin of MDA-MB-231 breast cancer cells. Molecules. 2015;20:15910–28.CrossRefPubMedGoogle Scholar
  4. 4.
    Leisching G, Loos B, Botha M, Engelbrecht AM. Bcl-2 confers survival in cisplatin treated cervical cancer cells: circumventing cisplatin dose-dependent toxicity and resistance. J Transl Med. 2015;13:328.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ye X, Zhang C, Chen Y, Zhou T. Upregulation of acetylcholinesterase mediated by p53 contributes to cisplatin-induced apoptosis in human breast cancer cell. J Cancer. 2015;6:48–53.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kartalou M, Essigmann JM. Mechanisms of resistance to cisplatin. Mutat Res. 2001;478:23–43.CrossRefPubMedGoogle Scholar
  7. 7.
    Konac E, Varol N, Kiliccioglu I, Bilen CY. Synergistic effects of cisplatin and proteasome inhibitor bortezomib on human bladder cancer cells. Oncol Lett. 2015;10:560–4.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Fang Z, Du R, Edwards A, Flemington EK, Zhang K. The sequence structures of human microRNA molecules and their implications. PLoS One. 2013;8, e54215.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Li L, Luo J, Wang B, Wang D, Xie X, Yuan L, et al. Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Mol Cancer. 2013;12:163.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhu E-D, Li N, Li B-S, Li W, Zhang W-J, Mao X-H, et al. miR-30b, down-regulated in gastric cancer, promotes apoptosis and suppresses tumor growth by targeting plasminogen activator inhibitor-1. PLoS One. 2014;9, e106049.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    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.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Yamamoto K, Ito S, Hanafusa H, Shimizu K, Ouchida M. Uncovering direct targets of MiR-19a involved in lung cancer progression. PLoS One. 2015;10, e0137887.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang ZC, Li YY, Wang HY, Fu S, Wang XP, Zeng MS, et al. Knockdown of miR-214 promotes apoptosis and inhibits cell proliferation in nasopharyngeal carcinoma. PLoS One. 2014;9, e86149.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Chen X, Liu J, Feng WK, Wu X, Chen SY. MiR-125b protects against ethanol-induced apoptosis in neural crest cells and mouse embryos by targeting Bak 1 and PUMA. Exp Neurol. 2015;271:104–11.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhou H, Forveille S, Sauvat A, Sica V, Izzo V, Durand S, et al. The oncolytic peptide LTX-315 kills cancer cells through Bax/Bak-regulated mitochondrial membrane permeabilization. Oncotarget. 2015;6:26599–614.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hamacher-Brady A, Brady NR. Bax/Bak-dependent, Drp1-independent targeting of X-linked inhibitor of apoptosis protein (XIAP) into inner mitochondrial compartments counteracts smac/DIABLO-dependent effector caspase activation. J Biol Chem. 2015;290:22005–18.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Peng H, Wang X, Zhang P, Sun T, Ren X, Xia Z. miR-27a promotes cell proliferation and metastasis in renal cell carcinoma. Int J Clin Exp Pathol. 2015;8(2):2259–66.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Li S, Li J, Fei BY, Shao D, Pan Y, Mo ZH, et al. MiR-27a promotes hepatocellular carcinoma cell proliferation through suppression of its target gene peroxisome proliferator-activated receptor γ. Chin Med J. 2015;128:941–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    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.PubMedGoogle Scholar
  22. 22.
    Amankwatia EB, Chakravarty P, Carey FA, Weidlich S, Steele RJ, Munro AJ, et al. MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms. Br J Cancer. 2015;112:1480–90.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    He Y, Wang J, Wang J, Yung VY, Hsu E, Li A, et al. MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2. Am J Cancer Res. 2015;5:1382–95.PubMedPubMedCentralGoogle Scholar
  24. 24.
    He H, Tian W, Chen H, Jiang K. MiR-944 functions as a novel oncogene and regulates the chemoresistance in breast cancer. Tumour Biol. 2015.Google Scholar
  25. 25.
    Karch J, Molkentin JD. Regulated necrotic cell death: the passive aggressive side of Bax and Bak. Circ Res. 2015;116:1800–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Leanza L, Venturini E, Kadow S, Carpinteiro A, Gulbins E, Becker KA. Targeting a mitochondrial potassium channel to fight cancer. Cell Calcium. 2015;58:131–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Dai H, Ding H, Meng XW, Peterson KL, Schneider PA, Karp JE, et al. Constitutive BAK activation as a determinant of drug sensitivity in malignant lymphohematopoietic cells. Genes Dev. 2015;29:2140–52.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25:4798–811.CrossRefPubMedGoogle Scholar
  29. 29.
    Vaux DL, Silke J. Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun. 2003;304:499–504.CrossRefPubMedGoogle Scholar
  30. 30.
    de Almagro MC, Vucic D. The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol. 2012;34:200–11.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Sumei Zhou
    • 1
  • Qidi Huang
    • 1
  • Shurong Zheng
    • 1
  • Kuailu Lin
    • 1
  • Jie You
    • 1
  • Xiaohua Zhang
    • 1
  1. 1.Surgical Oncology DepartmentThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou CityChina

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