Tumor Biology

, Volume 37, Issue 2, pp 2737–2748 | Cite as

A long non-coding RNA contributes to doxorubicin resistance of osteosarcoma

  • Chun-Lin Zhang
  • Kun-Peng Zhu
  • Guo-Qi Shen
  • Zhong-Sheng Zhu
Original Article


Long non-coding RNAs (lncRNAs) are emerging in molecular biology as crucial regulators of cancer. Although the aberrant expression of lncRNAs has been observed in osteosarcoma (OS), the molecular mechanisms underlying lncRNAs in doxorubicin resistance of OS still unknown. In the current study, we investigated a novel lncRNA, termed ODRUL (osteosarcoma doxorubicin-resistance related up-regulated lncRNA), and evaluated its role in the occurrence of doxorubicin resistance in OS. LncRNA microarray revealed that lncRNA ODRUL was the most up-regulated expressed in the doxorubicin-resistant OS cell line. Quantitative real-time PCR (qRT-PCR) confirmed that lncRNA ODRUL was higher in different doxorubicin-resistant OS cell lines and lower in different doxorubicin-sensitive OS cell lines. Moreover, we showed that lncRNA ODRUL was increased in specimens of OS patients with a poor chemoresponse and lung metastasis. We further demonstrated that lncRNA ODRUL inhibition could inhibit OS cell proliferation, migration, and partly reversed doxorubicin resistance in vitro. In addition, we found that the expression of classical drug resistance-related ATP-binding cassette, subfamily B, member 1 (ABCB1) gene was decreased after the lncRNA ODRUL knockdown. Thus, we concluded that lncRNA ODRUL may act as a pro-doxorubicin-resistant molecule through inducing the expression of the classical multidrug resistance-related ABCB1 gene in osteosarcoma cells .These findings may provide a novel target for reversing doxorubicin resistance in OS.


LncRNA ODRUL Osteosarcoma Doxorubicin resistance 



Long non-coding RNA




Osteosarcoma doxorubicin resistance-related up-regulated lncRNA



This project was supported by a Grant from the National Natural Science Foundation of China (NSFC No. 81572630), Shanghai Pujiang Program of Shanghai Science and Technology Commission (NO.13PJD023) and Shanghai Jiaotong University Medical-Engineering Cross Research Fund (NO.YG2012MS49).

Competing interests



  1. 1.
    Moore DD, Luu HH. Osteosarcoma. Cancer Treat Res. 2014;162:65–92.CrossRefPubMedGoogle Scholar
  2. 2.
    Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev. 2014;40:523–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol Biol. 2010;596:47–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics. 2013;193:651–69.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cheetham SW, Gruhl F, Mattick JS, Dinger ME. Long noncoding RNAs and the genetics of cancer. Br J Cancer. 2013;108:2419–25.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Xu M, Jin H, Xu CX, Bi WZ, Wang Y. MiR-34c inhibits osteosarcoma metastasis and chemoresistance. Med Oncol. 2014;31:972.CrossRefPubMedGoogle Scholar
  7. 7.
    Tano K, Akimitsu N. Long non-coding RNAs in cancer progression. Front Genet. 2012;3:219.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Spizzo R, Almeida MI, Colombatti A, Calin GA. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31:4577–87.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yang Y, Li H, Hou S, Hu B, Liu J, Wang J. The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. PLoS One. 2013;8, e65309.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. FEBS J. 2014;281:1750–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang Y, Zhang D, Wu K, Zhao Q, Nie Y, Long FD, et al. MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines. Mol Cell Biol. 2014;34:3182–93.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Milhem MM, Knutson T, Yang S, Zhu D, Wang X, Leslie KK and Meng X. Correlation of MTDH/AEG-1 and HOTAIR expression with metastasis and response to treatment in sarcoma patients. J Cancer Sci Ther. 2011;S5Google Scholar
  13. 13.
    Jiang M, Huang O, Xie Z, Wu S, Zhang X, Shen A, et al. A novel long non-coding RNA-ARA: adriamycin resistance-associated. Biochem Pharmacol. 2014;87:254–83.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhang XW, Bu P, Liu L, Zhang XZ, Li J. Overexpression of long non-coding RNA PVT1 in gastric cancer cells promotes the development of multidrug resistance. Biochem Biophys Res Commun. 2015;462:227–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu B, Han SM, Tang XY, Han L, Li CZ. Overexpressed FOXC2 in ovarian cancer enhances the epithelial-to-mesenchymal transition and invasion of ovarian cancer cells. Oncol Rep. 2014;31:2545–54.PubMedGoogle Scholar
  16. 16.
    Ren YH, Liu KJ, Wang M, Yu YN, Yang K, Chen Q, et al. De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells. Oncotarget. 2014;5:7093–104.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lee CH. Reversing agents for ATP-binding cassette (ABC) transporters: application in modulating multidrug resistance (MDR). Curr Med Chem Anticancer Agents. 2004;4:43–52.CrossRefPubMedGoogle Scholar
  18. 18.
    Lee CH. Reversing agents for ATP-binding cassette drug transporters. Methods Mol Biol. 2010;596:325–40.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim HJ, Im SA, Keam B, Ham HS, Lee KH, Kim TY, et al. ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy. Cancer Sci. 2015;106:86–93.CrossRefPubMedGoogle Scholar
  20. 20.
    Shang Y, Zhang Z, Liu Z, Feng B, Ren G, Li K, et al. miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1. Oncogene. 2014;33:3267–76.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang Z, Xia Q, Cui J, Diao Y, Li J. Reversion of P-glycoprotein-mediated multidrug resistance by diallyl trisulfide in a human osteosarcoma cell line. Oncol Rep. 2014;31:2720–6.PubMedGoogle Scholar
  22. 22.
    Okada T, Tanaka K, Nakatani F, Sakimura R, Matsunobu T, Li X, et al. Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing’s sarcoma cells. Int J Cancer. 2006;118:90–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Hang Q, Sun R, Jiang C, Li Y. Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression. Anticancer Drugs. 2015;26:632–40.PubMedGoogle Scholar
  24. 24.
    Tsang WP, Kwok TT. Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene. 2007;26:4877–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Stewart TA, Azimi I, Thompson EW, Roberts-Thomson SJ, Monteith GR. A role for calcium in the regulation of ATP-binding cassette, sub-family C, member 3 (ABCC3) gene expression in a model of epidermal growth factor-mediated breast cancer epithelial-mesenchymal transition. Biochem Biophys Res Commun. 2015;458:509–14.CrossRefPubMedGoogle Scholar
  26. 26.
    Juchum M, Gunther M, Laufer SA. Fighting cancer drug resistance: opportunities and challenges for mutation-specific EGFR inhibitors. Drug Resist Updat. 2015;20:12–28.CrossRefPubMedGoogle Scholar
  27. 27.
    Shien K, Yamamoto H, Soh J, Miyoshi S, Toyooka S. Drug resistance to EGFR tyrosine kinase inhibitors for non-small cell lung cancer. Acta Med Okayama. 2014;68:191–200.PubMedGoogle Scholar
  28. 28.
    Yan HQ, Huang XB, Ke SZ, Jiang YN, Zhang YH, Wang YN, et al. Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation. Cancer Sci. 2014;105:1220–7.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell. 2013;154:26–46.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010;329:689–93.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Chun-Lin Zhang
    • 1
  • Kun-Peng Zhu
    • 2
  • Guo-Qi Shen
    • 3
  • Zhong-Sheng Zhu
    • 1
  1. 1.Department of Orthopaedic SurgeryShanghai Tenth People’s Hospital Affiliated to Tongji UniversityShanghaiPeople’s Republic of China
  2. 2.Department of Orthopaedic SurgeryShanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong UniversityShanghaiPeople’s Republic of China
  3. 3.Department of Orthopaedic Surgery, Shanghai Sixth People’s HospitalSoochow UniversityShanghaiPeople’s Republic of China

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