Tumor Biology

, Volume 37, Issue 2, pp 2007–2014 | Cite as

The transmembrane transporter ABCC3 participates in liver cancer progression and is a potential biomarker

  • Gabriela Carrasco-Torres
  • Samia Fattel-Fazenda
  • Guadalupe Soledad López-Alvarez
  • Rebeca García-Román
  • Saúl Villa-Treviño
  • Verónica Rocío Vásquez-Garzón
Original Article


The poor prognosis, few available treatment options, and multidrug resistance present in hepatocellular carcinoma are major problems, and new early biomarkers are needed to reduce the liver cancer death rate. ATP-binding cassette sub-family C member 3 (Abcc3) is overexpressed in different cancers and is associated with multidrug resistance and a carcinogenic stem cell phenotype. We present evidence for the first time that ABCC3 is a potential sanguine biomarker and anticancer target in hepatocellular carcinoma. Abcc3 mRNA expression was elevated in liver nodules and tumors in rat hepatocarcinogenesis model. Accordingly, the ABCC3 protein was preferentially overexpressed within the nodules and tumors during hepatocellular carcinoma progression and was secreted into the bloodstream of rat hepatocarcinogenesis model. The ABCC3 protein was expressed in human hepatoma cells and, importantly, was also present in HepG2- and Huh7-conditioned media. Furthermore, ABCC3 was overexpressed in human hepatocellular carcinoma. This report is the first to describe liver overexpression of Abcc3 during the cancer initiation, promotion, and progression periods in rat hepatocarcinogenesis model and in human hepatocellular carcinoma.


ABCC3 Liver cancer Biomarker Plasma 



ATP-binding cassette sub-family C member 3


Hepatocellular carcinoma


ATP-binging cassette


Diethyl nitrosamine




γ-Glutamyl transpeptidase


Glutathione S-transferase P


Cancer stem cells



This work was supported by a scholarship (GCT), a grant contribution (178558) from CONACYT, and a postdoctoral scholarship, Multidisciplinary Project 3, from the SVT grant from CINVESTAV. We would like to acknowledge the animal technical support at UPEAL-CINVESTAV, including Rafael Leyva-Muñoz, Ricardo Gaxiola-Centeno, and Dr. Jorge Fernandez.


  1. 1.
    Villanueva A, Hernandez-Gea V, Llovet JM. Medical therapies for hepatocellular carcinoma: a critical view of the evidence. Nat Rev Gastroenterol Hepatol. 2013;10:34–42.CrossRefPubMedGoogle Scholar
  2. 2.
    Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Wang Y, Luo Q, Li Y, Wang H, Deng S, Wei S, et al. Quality assessment of clinical practice guidelines on the treatment of hepatocellular carcinoma or metastatic liver cancer. PLoS One. 2014;9:e103939.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Tsai CL, Koong AC, Hsu FM, Graber M, Chen IS, Cheng JC. Biomarker studies on radiotherapy to hepatocellular carcinoma. Oncology. 2013;84 Suppl 1:64–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Malagari K, Pomoni M, Sotirchos VS, Moschouris H, Bouma E, Charokopakis A, et al. Long term recurrence analysis post drug eluting bead (deb) chemoembolization for hepatocellular carcinoma (hcc). Hepato-Gastroenterology. 2013;60:1413–9.PubMedGoogle Scholar
  6. 6.
    Yang T, Zhang H, Cai SY, Shen YN, Yuan SX, Yang GS, et al. Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma. Ann Surg Oncol. 2013;20 Suppl 3:S644–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Cho EJ, Lee JH, Yoo JJ, Choi WM, Lee MJ, Cho Y, et al. Serum insulin-like growth factor-I level is an independent predictor of recurrence and survival in early hepatocellular carcinoma: a prospective cohort study. Clin Cancer Res. 2013;19:4218–27.CrossRefPubMedGoogle Scholar
  8. 8.
    Lee JS, Grisham JW, Thorgeirsson SS. Comparative functional genomics for identifying models of human cancer. Carcinogenesis. 2005;26:1013–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Siveen KS, Ahn KS, Ong TH, Shanmugam MK, Li F, Yap WN, et al. Y-tocotrienol inhibits angiogenesis-dependent growth of human hepatocellular carcinoma through abrogation of AKT/mTOR pathway in an orthotopic mouse model. Oncotarget. 2014;5:1897–911.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ganapathy-Kanniappan S, Kunjithapatham R, Torbenson MS, Rao PP, Carson KA, Buijs M, et al. Human hepatocellular carcinoma in a mouse model: assessment of tumor response to percutaneous ablation by using glyceraldehyde-3-phosphate dehydrogenase antagonists. Radiology. 2012;262:834–45.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Huynh H, Soo KC, Chow PK, Panasci L, Tran E. Xenografts of human hepatocellular carcinoma: a useful model for testing drugs. Clin Cancer Res. 2006;12:4306–14.CrossRefPubMedGoogle Scholar
  12. 12.
    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 J Int du Cancer. 2005;115:359–67.CrossRefGoogle Scholar
  13. 13.
    Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992;258:1650–4.CrossRefPubMedGoogle Scholar
  14. 14.
    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;96:6914–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hong X, Yang ZY, Wang M, Lu L, Li YH, Hao X, et al. Multidrug resistance-associated protein 3 and Bcl-2 contribute to multidrug resistance by vinorelbine in lung adenocarcinoma. Int J Mol Med. 2011;28:953–60.PubMedGoogle Scholar
  16. 16.
    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 J Int du Cancer. 2001;94:492–9.CrossRefGoogle Scholar
  17. 17.
    Wang XB, Wang SS, Zhang QF, Liu M, Li HL, Liu Y, et al. Inhibition of tetramethylpyrazine on P-gp, MRP2, MRP3 and MRP5 in multidrug resistant human hepatocellular carcinoma cells. Oncol Rep. 2010;23:211–5.PubMedGoogle Scholar
  18. 18.
    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;51:832–40.CrossRefPubMedGoogle Scholar
  19. 19.
    Benderra Z, Faussat AM, Sayada L, Perrot JY, Tang R, Chaoui D, et al. MRP3, BCRP, and P-glycoprotein activities are prognostic factors in adult acute myeloid leukemia. Clin Cancer Res. 2005;11:7764–72.CrossRefPubMedGoogle Scholar
  20. 20.
    A. Marche-Cova, S. Fattel-Fazenda, A. Rojas-Ochoa, E. Arce-Popoca, S. Villa-Trevino, Follow-up of GST-P during hepatocarcinogenesis with DEN-2AAF in F344 rats. Archives of medical research 26 Spec No (1995) S169-173.Google Scholar
  21. 21.
    Borel F, Han R, Visser A, Petry H, van Deventer SJ, Jansen PL, et al. Adenosine triphosphate-binding cassette transporter genes up-regulation in untreated hepatocellular carcinoma is mediated by cellular microRNAs. Hepatology. 2012;55:821–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Serrano MA, Macias RI, Briz O, Monte MJ, Blazquez AG, Williamson C, et al. Expression in human trophoblast and choriocarcinoma cell lines, BeWo, Jeg-3 and JAr of genes involved in the hepatobiliary-like excretory function of the placenta. Placenta. 2007;28:107–17.CrossRefPubMedGoogle Scholar
  23. 23.
    Mizukoshi E, Honda M, Arai K, Yamashita T, Nakamoto Y, Kaneko S. Expression of multidrug resistance-associated protein 3 and cytotoxic T cell responses in patients with hepatocellular carcinoma. J Hepatol. 2008;49:946–54.CrossRefPubMedGoogle Scholar
  24. 24.
    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. Scientific Rep. 2013;3:3120.Google Scholar
  25. 25.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 2009;59:225–49.CrossRefPubMedGoogle Scholar
  26. 26.
    Hoffmann K, Shibo L, Xiao Z, Longerich T, Buchler MW, Schemmer P. Correlation of gene expression of ATP-binding cassette protein and tyrosine kinase signaling pathway in patients with hepatocellular carcinoma. Anticancer Res. 2011;31:3883–90.PubMedGoogle Scholar
  27. 27.
    Sakulterdkiat T, Srisomsap C, Udomsangpetch R, Svasti J, Lirdprapamongkol K. Curcumin resistance induced by hypoxia in HepG2 cells is mediated by multidrug-resistance-associated proteins. Anticancer Res. 2012;32:5337–42.PubMedGoogle Scholar
  28. 28.
    Lun SW, Cheung ST, Cheung PF, To KF, Woo JK, Choy KW, et al. CD44+ cancer stem-like cells in EBV-associated nasopharyngeal carcinoma. PLoS One. 2012;7:e52426.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ma X, Zhou J, Zhang CX, Li XY, Li N, Ju RJ, et al. Modulation of drug-resistant membrane and apoptosis proteins of breast cancer stem cells by targeting berberine liposomes. Biomaterials. 2013;34:4452–65.CrossRefPubMedGoogle Scholar
  30. 30.
    Lee SH, Kim H, Hwang JH, Lee HS, Cho JY, Yoon YS, et al. Breast cancer resistance protein expression is associated with early recurrence and decreased survival in resectable pancreatic cancer patients. Pathol Int. 2012;62:167–75.CrossRefPubMedGoogle Scholar
  31. 31.
    Inokuchi A, Hinoshita E, Iwamoto Y, Kohno K, Kuwano M, Uchiumi T. Enhanced expression of the human multidrug resistance protein 3 by bile salt in human enterocytes. A transcriptional control of a plausible bile acid transporter. J Biol Chem. 2001;276:46822–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Noori-Daloii MR, Saffari M, Raoofian R, Yekaninejad M, Dinehkabodi OS, Noori-Daloii AR. The multidrug resistance pumps are inhibited by silibinin and apoptosis induced in K562 and KCL22 leukemia cell lines. Leukemia Res. 2014;38:575–80.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Gabriela Carrasco-Torres
    • 1
  • Samia Fattel-Fazenda
    • 1
  • Guadalupe Soledad López-Alvarez
    • 1
  • Rebeca García-Román
    • 2
  • Saúl Villa-Treviño
    • 1
  • Verónica Rocío Vásquez-Garzón
    • 1
    • 3
  1. 1.Departamento de Biología CelularCentro de Investigación y de Estudios Avanzados del IPN (CINVESTAV)México D.F.Mexico
  2. 2.Instituto de Salud PúblicaUniversidad VeracruzanaVeracruzMexico
  3. 3.Cátedra-CONACYT, Facultad de Medicina y CirugíaUniversidad Autónoma “Benito Juárez” de OaxacaOaxaca de JuárezMexico

Personalised recommendations