Skip to main content

Advertisement

SpringerLink
Log in

miR-668 enhances the radioresistance of human breast cancer cell by targeting IκBα

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

A large proportion of breast cancer patients are resistant to radiotherapy, which is a mainstay treatment for this malignancy, but the mechanisms of radioresistance remain unclear.

Methods and materials

To evaluate the role of miRNAs in radioresistance, we established two radioresistant breast cancer cell lines MCF-7R and T-47DR derived from parental MCF-7 and T-47D. Moreover, miRNA microarray, quantitative RT-PCR analysis, luciferase reporter assay and western blotting were used.

Results

We found that miR-668 was most abundantly expressed in radioresistant cells MCF-7R and T-47DR. miR-668 knockdown reversed radioresistance of MCF-7R and T-47DR, miR-668 overexpression enhanced radioresistance of MCF-7 and T-47D cells. Mechanically, bioinformatics analysis combined with experimental analysis demonstrated IκBα, a tumor-suppressor as well as an NF-κB inhibitor, was a direct target of miR-668. Further, miR-668 overexpression inhibited IκBα expression, activated NF-κB, thus, increased radioresistance of MCF-7 and T-47D cells. Conversely, miR-668 knockdown restored IκBα expression, suppressed NF-κB, increased radiosensitivity of MCF-7R and T-47DR cells.

Conclusion

Our findings suggest miR-668 is involved in the radioresistance of breast cancer cells and miR-668-IκBα-NF-κB axis may be a novel candidate for developing rational therapeutic strategies for human breast cancer treatment.

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

Similar content being viewed by others

References

  1. Ahn SJ, Choi C, Choi YD, Kim YC, Kim KS, Oh IJ, et al. Microarray analysis of gene expression in lung cancer cell lines treated by fractionated irradiation. Anticancer Res. 2014;34(9):4939–48.

    CAS  PubMed  Google Scholar 

  2. Burstein HJ, Morrow M. Nodal irradiation after breast-cancer surgery in the era of effective adjuvant therapy. N Engl J Med. 2015;373(4):379–81.

    Article  CAS  PubMed  Google Scholar 

  3. But-Hadzic J, Bilban-Jakopin C, Hadzic V. The role of radiation therapy in locally advanced breast cancer. Breast J. 2010;16(2):183–8.

    Article  PubMed  Google Scholar 

  4. Chen XY, Wang Z, Li B, Zhang YJ, Li YY. Pim-3 contributes to radioresistance through regulation of the cell cycle and DNA damage repair in pancreatic cancer cells. Biochem Biophys Res Commun. 2016;473(1):296–302.

    Article  CAS  PubMed  Google Scholar 

  5. Djuranovic S, Nahvi A, Green R. A parsimonious model for gene regulation by miRNAs. Science. 2011;331(6017):550–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fu ZC, Wang FM, Cai JM. Gene expression changes in residual advanced cervical cancer after radiotherapy: indicators of poor prognosis and radioresistance? Med Sci Monit. 2015;21:1276–87.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gong C, Nie Y, Qu S, Liao JY, Cui X, Yao H, et al. miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors. Cancer Res. 2014;74(16):4341–52.

    Article  CAS  PubMed  Google Scholar 

  8. Gong C, Yao Y, Wang Y, Liu B, Wu W, Chen J, et al. Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer. J Biol Chem. 2011;286(21):19127–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hein AL, Post CM, Sheinin YM, Lakshmanan I, Natarajan A, Enke CA, et al. RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment. Oncogene. 2016;35(49):6319–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huang X, Taeb S, Jahangiri S, Korpela E, Cadonic I, Yu N, et al. miR-620 promotes tumor radioresistance by targeting 15-hydroxyprostaglandin dehydrogenase (HPGD). Oncotarget. 2015;6(26):22439–51.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim W, Youn H, Kang C, Youn B. Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells. Apoptosis. 2015;20(9):1242–52.

    Article  CAS  PubMed  Google Scholar 

  12. Kurth I, Hein L, Mabert K, Peitzsch C, Koi L, Cojoc M, et al. Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma. Oncotarget. 2015;6(33):34494–509.

    PubMed  PubMed Central  Google Scholar 

  13. Lan F, Yue X, Ren G, Li H, Ping L, Wang Y, et al. miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-kappaB signaling pathway. Int J Radiat Oncol Biol Phys. 2015;91(1):73–81.

    Article  CAS  PubMed  Google Scholar 

  14. Li J, Huang H, Sun L, Yang M, Pan C, Chen W, et al. MiR-21 indicates poor prognosis in tongue squamous cell carcinomas as an apoptosis inhibitor. Clin Cancer Res. 2009;15(12):3998–4008.

    Article  CAS  PubMed  Google Scholar 

  15. Liang DH, El-Zein R, Dave B. Autophagy inhibition to increase radiosensitization in breast cancer. J Nucl Med Radiat Ther. 2015;6(5):1–13.

    Article  Google Scholar 

  16. Liang K, Lu Y, Jin W, Ang KK, Milas L, Fan Z. Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther. 2003;2(11):1113–20.

    CAS  PubMed  Google Scholar 

  17. Liao H, Xiao Y, Hu Y, Xiao Y, Yin Z, Liu L. microRNA-32 induces radioresistance by targeting DAB2IP and regulating autophagy in prostate cancer cells. Oncol Lett. 2015;10(4):2055–62.

    PubMed  PubMed Central  Google Scholar 

  18. Mazurik VK, Moroz BB. Problems of radiobiology and p53 protein. Radiat Biol Radioecol. 2001;41(5):548–72.

    CAS  Google Scholar 

  19. McIlrath J, Bouffler SD, Samper E, Cuthbert A, Wojcik A, Szumiel I, et al. Telomere length abnormalities in mammalian radiosensitive cells. Cancer Res. 2001;61(3):912–5.

    CAS  PubMed  Google Scholar 

  20. Mehta M, Basalingappa K, Griffith JN, Andrade D, Babu A, Amreddy N, et al. HuR silencing elicits oxidative stress and DNA damage and sensitizes human triple-negative breast cancer cells to radiotherapy. Oncotarget. 2016;7(40):64820–35.

    PubMed  PubMed Central  Google Scholar 

  21. Oh ET, Byun MS, Lee H, Park MT, Jue DM, Lee CW, et al. Aurora-A contributes to radioresistance by increasing NF-κB DNA binding. Radiat Res. 2010;174(3):265–73.

    Article  CAS  PubMed  Google Scholar 

  22. Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci USA. 2001;98(4):1676–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Qu C, Liang Z, Huang J, Zhao R, Su C, Wang S, et al. MiR-205 determines the radioresistance of human nasopharyngeal carcinoma by directly targeting PTEN. Cell Cycle. 2012;11(4):785–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Qu JQ, Yi HM, Ye X, Li LN, Zhu JF, Xiao T, et al. MiR-23a sensitizes nasopharyngeal carcinoma to irradiation by targeting IL-8/Stat3 pathway. Oncotarget. 2015;6(29):28341–56.

    Article  PubMed  Google Scholar 

  25. Rhoads MG, Kandarian SC, Pacelli F, Doglietto GB, Bossola M. Expression of NF-κB and IκB proteins in skeletal muscle of gastric cancer patients. Eur J Cancer. 2010;46(1):191–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ropars V, Despouy G, Stern MH, Benichou S, Roumestand C, Arold ST. The TCL1A oncoprotein interacts directly with the NF-κB inhibitor IκB. PLoS ONE. 2009;4(8):e6567.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  28. Vandenboom Ii TG, Li Y, Philip PA, Sarkar FH. MicroRNA and cancer: tiny molecules with major implications. Curr Genom. 2008;9(2):97–109.

    Article  Google Scholar 

  29. Yu F, Deng H, Yao H, Liu Q, Su F, Song E. Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells. Oncogene. 2010;29(29):4194–204.

    Article  CAS  PubMed  Google Scholar 

  30. 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(6):1109–23.

    Article  CAS  PubMed  Google Scholar 

  31. Zand H, Rahimipour A, Salimi S, Shafiee SM. Docosahexaenoic acid sensitizes Ramos cells to Gamma-irradiation-induced apoptosis through involvement of PPAR-gamma activation and NF-κB suppression. Mol Cell Biochem. 2008;317(1–2):113–20.

    Article  CAS  PubMed  Google Scholar 

  32. Zhao F, Ming J, Zhou Y, Fan L. Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation. Cancer Chemother Pharmacol. 2016;77(5):963–72.

    Article  CAS  PubMed  Google Scholar 

  33. Zheng L, Zhang Y, Liu Y, Zhou M, Lu Y, Yuan L, et al. MiR-106b induces cell radioresistance via the PTEN/PI3K/AKT pathways and p21 in colorectal cancer. J Transl Med. 2015;13:252–65.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant [2013] 163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology; Grant KLB09001 from the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes; Grant from Guangdong Science and Technology Department (2015B050501004, 2014J4100170). This work was also supported by grants from the National Natural Science Foundation of China (81372819, 81572596, U1601223), Specialized Research Fund for the Doctoral Program of Higher Education (20120171110075), and Sun Yat-Sen University (13ykzd14).

Author information

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China

    Ming Luo, Ling Ding, Qingjian Li & Herui Yao

  2. Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong, China

    Ming Luo, Ling Ding, Qingjian Li & Herui Yao

  3. Breast Tumor Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China

    Herui Yao

Authors
  1. Ming Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qingjian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Herui Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Herui Yao.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, M., Ding, L., Li, Q. et al. miR-668 enhances the radioresistance of human breast cancer cell by targeting IκBα. Breast Cancer 24, 673–682 (2017). https://doi.org/10.1007/s12282-017-0756-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-017-0756-1

Keywords

Search

Navigation