Skip to main content

Advertisement

SpringerLink
Log in

Linc-ROR induces epithelial-mesenchymal transition and contributes to drug resistance and invasion of breast cancer cells

  • Original Article
  • Published:
Tumor Biology

Abstract

We aimed to investigate the role of large intergenic noncoding RNA regulator of reprogramming (linc-ROR) in the chemotherapy resistance of human breast cancer (BC) cells and its mechanism. A total of 142 patients diagnosed with BC in the First Affiliated Hospital, Zhejiang University between January 2012 and January 2014 were enrolled in our study. The BC tissues and the adjacent normal tissues (5 cm away from tumor tissue) of the enrolled patients were selected, and human BC cell lines (MCF10A, SK-BR-3, MCF-7, Bcap-37, MDA-MB-231, and T47D) were also selected. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay, and Transwell were applied in our study. Expression level of linc-ROR messenger RNA (mRNA) in BC tissues was clearly higher than that in adjacent normal tissues, and significant difference was found between expression level of linc-ROR mRNA and lymph node metastasis (all P < 0.05). Linc-ROR was highly expressed in others BC cell lines compared with that in immortalized mammary epithelial cells (MECs) MCF10A (both P < 0.05), while MDA-MB231 cell presented the higher expression (P < 0.001). Under different concentrations of 5-FU and paclitaxel in MDA-MB231 cell, E-cadherin mRNA and protein expressions increased gradually with the increase of concentrations, and Vimentin and N-cadherin mRNA and protein expressions decreased gradually with the decrease of concentrations (all P < 0.05). Compared with shCtrl group, MDA-MB231 cell in shROR group presented higher sensibility of 5-FU and paclitaxel with increased E-cadherin expression, decreased Vimentin and N-cadherin expression and invasion ability (all P < 0.05). Compared with vector cell, overexpressed linc-ROR cell presented decreased sensibility of 5-FU and paclitaxel with decreased E-cadherin expression, increased Vimentin, N-cadherin expression, and invasion ability (all P < 0.05). Our study demonstrated that linc-ROR is an important marker for multidrug resistance of BC, and its up-regulation is important for chemotherapy tolerance and invasion of BC.

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. Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. 2012;44(3):312–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stuckey A. Breast cancer: epidemiology and risk factors. Clin Obstet Gynecol. 2011;54(1):96–102.

    Article  PubMed  Google Scholar 

  3. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009;36(3):237–49.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fredholm H, Eaker S, Frisell J, Holmberg L, Fredriksson I, Lindman H. Breast cancer in young women: poor survival despite intensive treatment. PLoS One. 2009;4(11), e7695.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kaminska M, Ciszewski T, Lopacka-Szatan K, Miotla P, Staroslawska E. Breast cancer risk factors. Prz Menopauzalny. 2015;14(3):196–202.

    PubMed  PubMed Central  Google Scholar 

  6. Curigliano G, Spitaleri G, Dettori M, Locatelli M, Scarano E, Goldhirsch A. Vaccine immunotherapy in breast cancer treatment: promising, but still early. Expert Rev Anticancer Ther. 2007;7(9):1225–41.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang W, Feng M, Zheng G, Chen Y, Wang X, Pen B, et al. Chemoresistance to 5-fluorouracil induces epithelial-mesenchymal transition via up-regulation of snail in mcf7 human breast cancer cells. Biochem Biophys Res Commun. 2012;417(2):679–85.

    Article  CAS  PubMed  Google Scholar 

  8. Liang Z, Wu H, Xia J, Li Y, Zhang Y, Huang K, et al. Involvement of mir-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem Pharmacol. 2010;79(6):817–24.

    Article  CAS  PubMed  Google Scholar 

  9. Consortium EP, Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, et al. Identification and analysis of functional elements in 1% of the human genome by the encode pilot project. Nature. 2007;447(7146):799–816.

    Article  Google Scholar 

  10. Hou P, Zhao Y, Li Z, Yao R, Ma M, Gao Y, et al. Lincrna-ror induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis. 2014;5, e1287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding rnas in mammals. Nature. 2009;458(7235):223–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Breaker RR. Prospects for riboswitch discovery and analysis. Mol Cell. 2011;43(6):867–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wilusz JE, Sunwoo H, Spector DL. Long noncoding rnas: functional surprises from the RNA world. Genes Dev. 2009;23(13):1494–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C, et al. Ultraconserved regions encoding ncrnas are altered in human leukemias and carcinomas. Cancer Cell. 2007;12(3):215–29.

    Article  CAS  PubMed  Google Scholar 

  15. Huarte M, Rinn JL. Large non-coding RNAs: missing links in cancer? Hum Mol Genet. 2010;19(R2):R152–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense rna. Nature. 2008;451(7175):202–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Loewer S, Cabili MN, Guttman M, Loh YH, Thomas K, Park IH, et al. Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells. Nat Genet. 2010;42(12):1113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhu Y, Luo M, Brooks Mea. Biological and clinical significance of cancer stem cell plasticity. Clinical and Translational Medicine. 2014;3(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, et al. Endogenous mirna sponge lincrna-ror regulates oct4, nanog, and sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013;25(1):69–80.

    Article  CAS  PubMed  Google Scholar 

  20. M PN. World medical association publishes the revised Declaration of Helsinki. Natl Med J India. 2014;27(1):56.

  21. Penault-Llorca F. Comments on the new American Joint Committee on Cancer TNM staging for breast cancer. What’s new for the pathologist? Ann Pathol. 2003;23(6):492–5.

    PubMed  Google Scholar 

  22. Tuo YL, Li XM, Luo J. Long noncoding rna uca1 modulates breast cancer cell growth and apoptosis through decreasing tumor suppressive mir-143. Eur Rev Med Pharmacol Sci. 2015;19(18):3403–11.

    PubMed  Google Scholar 

  23. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 2007;608:1–22.

    Article  CAS  PubMed  Google Scholar 

  24. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding rnas. Cell. 2009;136(4):629–41.

    Article  CAS  PubMed  Google Scholar 

  25. Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, et al. LincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 2011;477(7364):295–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saison C, Helias V, Ballif BA, Peyrard T, Puy H, Miyazaki T, et al. Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system junior. Nat Genet. 2012;44(2):174–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chang JT, Mani SA. Sheep, wolf, or werewolf: cancer stem cells and the epithelial-to-mesenchymal transition. Cancer Lett. 2013;341(1):16–23.

    Article  CAS  PubMed  Google Scholar 

  28. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pauli A, Valen E, Lin MF, Garber M, Vastenhouw NL, Levin JZ, et al. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res. 2012;22(3):577–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68(4):989–97.

    Article  CAS  PubMed  Google Scholar 

  31. Hernandez-Aya LF, Gonzalez-Angulo AM. Adjuvant systemic therapies in breast cancer. Surg Clin N Am. 2013;93(2):473–91.

    Article  PubMed  Google Scholar 

  32. Vinod BS, Antony J, Nair HH, Puliyappadamba VT, Saikia M, Narayanan SS, et al. Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5-fluorouracil. Cell Death Dis. 2013;4, e505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A, et al. Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 2007;31(2):277–83.

    CAS  PubMed  Google Scholar 

  34. Du F, Wu X, Liu Y, Wang T, Qi X, Mao Y, et al. Acquisition of paclitaxel resistance via PI3K-dependent epithelial-mesenchymal transition in A2780 human ovarian cancer cells. Oncol Rep. 2013;30(3):1113–8.

    CAS  PubMed  Google Scholar 

  35. Wu Q, Wang R, Yang Q, Hou X, Chen S, Hou Y, et al. Chemoresistance to gemcitabine in hepatoma cells induces epithelial-mesenchymal transition and involves activation of PDGF-D pathway. Oncotarget. 2013;4(11):1999–2009.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This research is funded by the Zhejiang Provincial Natural Science Foundation (LY13H160006). We would like to acknowledge the reviewers for their helpful comments on this paper.

Author information

Authors and Affiliations

  1. Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University, No.79 Qingchun Road, Hangzhou, 310000, China

    Yao-Min Chen, Yu Liu, Hai-Yan Wei, Ke-Zhen Lv & Peifen Fu

Authors
  1. Yao-Min Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai-Yan Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ke-Zhen Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peifen Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peifen Fu.

Ethics declarations

This study was approved by the Ethical Committee of the First Affiliated Hospital, Zhejiang University. Written informed consents were obtained from all study subjects. This study complied with the guidelines and principles of the Declaration of Helsinki [20].

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, YM., Liu, Y., Wei, HY. et al. Linc-ROR induces epithelial-mesenchymal transition and contributes to drug resistance and invasion of breast cancer cells. Tumor Biol. 37, 10861–10870 (2016). https://doi.org/10.1007/s13277-016-4909-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-4909-1

Keywords

Search

Navigation