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ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells

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Tumor Biology

Abstract

There is increasing evidence supporting the cancer stem cell (CSC) hypothesis, which suggests that a population of tumor cells with stem cell characteristics is responsible for tumor growth, resistance, and recurrence as well as drug resistance. In colorectal cancer, the CD133 antigen defines distinct cell subpopulations that are rich in tumor-initiating cells; however, the drug resistance properties of these CD133-positive cells have not been well defined. The breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is present on the plasma membrane of many types of human cancer cells and contributes to multidrug resistance during chemotherapy. The results of the present study showed that ABCG2 is expressed in CD133-positive CSCs from human colorectal tumors. Furthermore, the downregulation of ABCG2 expression inhibited the self-renewal capacity of these cells, and significantly enhanced the efficacy of chemotherapy-induced apoptosis in LS174T colon adenocarcinoma cells and CD133-positive colorectal carcinoma cells. Together, these data show that ABCG2 expression correlates with the presence of CD133-positive cancer cells, and thus is a possible therapeutic target for colorectal cancer.

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References

  1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics. CA Cancer J Clin. 2001;51:15–36.

    Article  CAS  PubMed  Google Scholar 

  2. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature. 2007;445:106–10.

    Article  PubMed  Google Scholar 

  3. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon cancer-initiating cells. Nature. 2007;445:111–5.

    Article  CAS  PubMed  Google Scholar 

  4. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1:389–402.

    Article  CAS  PubMed  Google Scholar 

  5. Vermeulen L, Todaro M, de Sousa Mello F, Sprick MR, Kemper K, Perez Alea M, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A. 2008;105:13427–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Horst D, Scheel SK, Liebmann S, Neumann J, Maatz S, Kirchner T, Jung A. The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol. 2009;219:427–34.

    Article  CAS  PubMed  Google Scholar 

  7. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol. 2009;16:3488–98.

    Article  PubMed  Google Scholar 

  8. Artells R, Moreno I, Diaz T, Martinez F, Gel B, Navarro A, Ibeas R, Moreno J, Monzo M. Tumour CD133 mRNA expression and clinical outcome in surgically resected colorectal cancer patients. Eur J Cancer. 2010;46:642–9.

    Article  CAS  PubMed  Google Scholar 

  9. Chen H, Zhao JY, Qian XC, Cheng ZY, Liu Y, Wang Z. RASAL1 attenuates gastric carcinogenesis in nude mice by blocking RAS/ERK signaling. Asian Pac J Cancer Prev. 2015;16(3):1077–82.

    Article  PubMed  Google Scholar 

  10. de Jonge-Peeters SD, Kuipers F, de Vries EG, Vellenga E. ABC transporter expression in hematopoietic stem cells and the role in AML drug resistance. Crit Rev Oncol Hematol. 2007;62(3):214–26.

    Article  PubMed  Google Scholar 

  11. Polgar O, Robey RW, Bates SE. ABCG2: structure, function and role in drug response. Expert Opin Drug Metab Toxicol. 2008;4(1):1–15.

    Article  CAS  PubMed  Google Scholar 

  12. Honjo Y, Hrycyna CA, Yan QW, Medina-Perez WY, Robey RW, van de Laar A, et al. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res. 2001;61(18):6635–9.

    CAS  PubMed  Google Scholar 

  13. Meyer ZU, Schwabedissen HE, Kroemer HK. In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2). Handb Exp Pharmacol. 2011;201:325–71.

    Article  Google Scholar 

  14. Yang JP, Liu Y, Zhong W, Yu D, Wen LJ, Jin CS. Chemoresistance of CD133+ cancer stem cells in laryngeal carcinoma. Chin Med J. 2011;124(7):1055–60.

    CAS  PubMed  Google Scholar 

  15. Mannelli G, Magnelli L, Deganello A, Busoni M, Meccariello G, Parrinello G, et al. Detection of putative stem cell markers, CD44/CD133, in primary and lymph node metastases in head and neck squamous cell carcinomas. A preliminary immunohistochemical and in vitro study. Clin Otolaryngol. 2015;40(4):312–20.

    Article  CAS  PubMed  Google Scholar 

  16. Chen K, Huang YH, Chen JL. Understaning and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34(6):732–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee MR, Ji SY, Mia-Jan K, et al. Chemoresistance of CD133+ colon cancer may be related with increased survivin expression. Biochem Bioph Res Co. 2015;463:229–34.

  18. Hongo K, Tanaka J, Tsuno NH, Kawai K, Nishikawa T, et al. CD133 (−) cells, derived from a single human colon cancer cell line, are more resistant to 5-fluorouracil (FU) than CD133 (+) cells, dependent on the beta1-integrin signaling. J Surg Res. 2012;175:278–88.

    Article  CAS  PubMed  Google Scholar 

  19. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A. 1998;95:15665–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yan HC, Fang LS, Xu J, et al. The identification of the biological characteristics of human ovarian cancer stem cells. Eur Rev Med Pharmacol Sci. 2014;18:3497–503.

    CAS  PubMed  Google Scholar 

  21. Garson K, Vanderhyden BC. Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm. Reproduction. 2015;149:R59–70.

    Article  CAS  PubMed  Google Scholar 

  22. Bhattacharya S, Das A, Mallya K, Ahmad I. Maintenance of retinal stem cells by Abcg2 is regulated by notch signaling. J Cell Sci. 2007;120:2652–62.

    Article  CAS  PubMed  Google Scholar 

  23. Liang S-C, Yang C-Y, Tseng J-Y, et al. ABCG2 localizes to the nucleus and modulates CDH1 expression in lung cancer cells. Neoplasia. 2015;17:265–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao X, Mi Y, Ma Y. LEF1 regulates glioblastoma cell proliferation, migration, invasion, and cancer stem-like cell self-renewal. Tumor Biol. 2014;35:11505–11.

    Article  CAS  Google Scholar 

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Acknowledgments

This work is supported by the China Natural Science Foundation (No. 81260309), Ningxia Province Science Research Foundation of China (No. 79), and the Ningxia Medical University Research Foundation of China (No. XM201135).

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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, School of Basic Medical Science, Peking University Health Science Center, Beijing, 100191, China

    Lijun Ma & Hongquan Zhang

  2. Ningxia Human Stem Cell Institute, the General Hospital of Ningxia Medical University, Yinchuan, 750004, China

    Lijun Ma, Ting Liu, Yiran Jin, Jun Wei & Yinxue Yang

Authors
  1. Lijun Ma
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  2. Ting Liu
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  3. Yiran Jin
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  4. Jun Wei
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  5. Yinxue Yang
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  6. Hongquan Zhang
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Corresponding authors

Correspondence to Yinxue Yang or Hongquan Zhang.

Ethics declarations

Thirty-six primary tumor specimens were collected from tumors surgically removed from patients diagnosed to have colorectal cancers in the surgical center of the General Hospital of Ningxia Medical University, and according to the ethical standards of the institutional committee approved by Ningxia Medical University. Informed consent was obtained from all patients included in the study.

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Ma, L., Liu, T., Jin, Y. et al. ABCG2 is required for self-renewal and chemoresistance of CD133-positive human colorectal cancer cells. Tumor Biol. 37, 12889–12896 (2016). https://doi.org/10.1007/s13277-016-5209-5

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  • DOI: https://doi.org/10.1007/s13277-016-5209-5

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