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Tumor Biology

, Volume 37, Issue 6, pp 8367–8374 | Cite as

Overexpression of ABCC3 promotes cell proliferation, drug resistance, and aerobic glycolysis and is associated with poor prognosis in urinary bladder cancer patients

  • Xuejun Liu
  • Dongwei Yao
  • Cheng Liu
  • Yunjian Cao
  • Qiurong Yang
  • Zhichao Sun
  • Duo Liu
Original Article

Abstract

Human urinary bladder cancer (UBC) is the one of the most common malignancies worldwide and occurs at a higher frequency in male individuals. ATP-binding cassette, subfamily C, member 3 (ABCC3), a member of the ABC transporter family, is highly expressed in tumor cells, where it actively effluxes a broad spectrum of metabolites. However, the expression and role of ABCC3 in human UBC remains unclear. Our study aimed to identify the expression status of ABCC3 in UBC cases and investigate the biological effects on UBC in cells. We found that both mRNA and protein levels of ABCC3 were significantly higher in UBC tissues than normal tissues. Immunochemistry evaluation of ABCC3 expression in 122 UBC clinical specimens showed that high expression of ABCC3 had a positive correlation with UBC tumor size, advanced tumor node metastasis stage, and malignant histology. Moreover, high ABCC3 expression was linked to poor overall survival in UBC. ABCC3 effects on cell proliferation and drug resistance were measured by colony formation and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays. ABCC3-knockdown cells showed a significant decrease in cell growth and drug resistance. RNA interference of ABCC3 also caused downregulation of lactate dehydrogenase A (LDHA), which positively correlated with ABCC3 expression in UBC specimens. In addition, cancer cell glycolytic ability was decreased upon ABCC3 knockdown. The activity of LDHA was also abrogated in ABCC3-deficient UBC cells, and the blockade of LDHA increased UBC cells sensitivity to Cis-diamine dichloroplatinum (CDDP). In summary, our study suggests ABCC3 is an important oncoprotein involved in glycolysis and drug resistance. These data also indicates that ABCC3 could be a potential prognostic marker and promising therapeutic target in UBC.

Keywords

Urinary bladder cancer ABCC3 Prognostic marker Cell growth Drug sensitivity Aerobic glycolysis 

Notes

Acknowledgments

The study was supported by a grant from the Young Professionals Foundation of The Second People’s Hospital of Lianyungang. We thank the anonymous reviewers for their constructive comments.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Vishnu P, Mathew J, Tan WW. Current therapeutic strategies for invasive and metastatic bladder cancer. Onco Targets Ther. 2011;4:97–113.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, Ribal MJ, et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Actas Urol Esp. 2012;36(8):449–60.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen HH, Kuo MT. Role of glutathione in the regulation of Cisplatin resistance in cancer chemotherapy. Met Based Drugs. 2010. doi: 10.1155/2010/430939.
  6. 6.
    Schmid SC, Schuster T, Horn T, Gschwend J, Treiber U, Weirich G. Utility of ATP7B in prediction of response to platinum-based chemotherapy in urothelial bladder cancer. Anticancer Res. 2013;33(9):3731–7.PubMedGoogle Scholar
  7. 7.
    Hoffmann AC, Wild P, Leicht C, Bertz S, Danenberg KD, Danenberg PV, et al. MDR1 and ERCC1 expression predict outcome of patients with locally advanced bladder cancer receiving adjuvant chemotherapy. Neoplasia. 2010;12(8):628–36.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ozcan MF, Dizdar O, Dincer N, Balcı S, Guler G, Gok B, et al. Low ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinum-based neoadjuvant chemotherapy. Urol Oncol. 2013;31(8):17.CrossRefGoogle Scholar
  9. 9.
    Zhang H, Fu LW. Multidrug resistance-associated proteins and their roles in multidrug resistance. Yao Xue Xue Bao. 2011;46(5):479–86.PubMedGoogle Scholar
  10. 10.
    Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JM, Smith AJ, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A. 1999;96(12):6914–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nies AT, Konig J, Pfannschmidt M, Klar E, Hofmann WJ, Keppler D. Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int J Cancer. 2001;94(4):492–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Young LC, Campling BG, Cole SP, Deeley RG, Gerlach JH. Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels. Clin Cancer Res. 2001;7(6):1798–804.PubMedGoogle Scholar
  13. 13.
    Partanen L, Staaf J, Tanner M, Tuominen VJ, Borg A, Isola J. Amplification and overexpression of the ABCC3 (MRP3) gene in primary breast cancer. Genes Chromosomes Cancer. 2012;51(9):832–40.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao Y, Lu H, Yan A, Yang Y, Meng Q, Sun L, et al. ABCC3 as a marker for multidrug resistance in non-small cell lung cancer. Sci Rep. 2013;3:3120.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Ros JE, Libbrecht L, Geuken M, Jansen PL, Roskams TA. High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease. J Pathol. 2003;200(5):553–60.CrossRefPubMedGoogle Scholar
  16. 16.
    Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall HU, Zatloukal K, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol. 2003;38(6):717–27.CrossRefPubMedGoogle Scholar
  17. 17.
    Hardwick RN, Fisher CD, Canet MJ, Scheffer GL, Cherrington NJ. Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease. Drug Metab Dispos. 2011;39(12):2395–402.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Konig J, Hartel M, Nies AT, Martignoni ME, Guo J, Buchler MW, et al. Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int J Cancer. 2005;115(3):359–67.CrossRefPubMedGoogle Scholar
  19. 19.
    Kuan CT, Wakiya K, Herndon 2nd JE, Lipp ES, Pegram CN, Riggins GJ, et al. MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer. 2010;10:468.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Jones W, Bianchi K. Aerobic glycolysis: beyond proliferation. Front Immunol. 2015;6:227.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lu H, Li X, Luo Z, Liu J, Fan Z. Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A. Mol Cancer Ther. 2013;12(10):2187–99.CrossRefPubMedGoogle Scholar
  22. 22.
    Gogalic S, Sauer U, Doppler S, Preininger C. Bladder cancer biomarker array to detect aberrant levels of proteins in urine. Analyst. 2015;140(3):724–35.CrossRefPubMedGoogle Scholar
  23. 23.
    Scheffer GL, Kool M, de Haas M, de Vree JM, Pijnenborg AC, Bosman DK, et al. Tissue distribution and induction of human multidrug resistant protein 3. Lab Invest. 2002;82(2):193–201.CrossRefPubMedGoogle Scholar
  24. 24.
    Decleves X, Fajac A, Lehmann-Che J, Tardy M, Mercier C, Hurbain I, et al. Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines. Int J Cancer. 2002;98(2):173–80.CrossRefPubMedGoogle Scholar
  25. 25.
    Haga S, Hinoshita E, Ikezaki K, Fukui M, Scheffer GL, Uchiumi T, et al. Involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma. Jpn J Cancer Res. 2001;92(2):211–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–82.CrossRefPubMedGoogle Scholar
  27. 27.
    Giannoudis A, Davies A, Harris RJ, Lucas CM, Pirmohamed M, Clark RE. The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia. Leukemia. 2014;28(6):1360–3.CrossRefPubMedGoogle Scholar
  28. 28.
    Liu S, Yi Z, Ling M, Shi J, Qiu Y, Yang S. Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy. Tumour Biol. 2014;35(10):9897–904.CrossRefPubMedGoogle Scholar
  29. 29.
    Caronia D, Patino-Garcia A, Perez-Martinez A, Pita G, Moreno LT, Zalacain-Diez M, et al. Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: a pharmacogenetic study. PLoS One. 2011;6(10):e26091.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Xuejun Liu
    • 1
  • Dongwei Yao
    • 1
  • Cheng Liu
    • 1
  • Yunjian Cao
    • 2
  • Qiurong Yang
    • 1
  • Zhichao Sun
    • 3
  • Duo Liu
    • 1
  1. 1.Department of UrologyThe Second People’s Hospital of LianyungangHaizhouChina
  2. 2.Department of NursingThe Second People’s Hospital of LianyungangHaizhouChina
  3. 3.Department of PathologyThe Second People’s Hospital of LianyungangHaizhouChina

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