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miR-145 Inhibits Migration and Invasion of Glioma Stem Cells by Targeting ABCG2


Despite advances in clinical therapies and technologies, the prognosis for patients with malignant glioma is poor. Our previous research demonstrated that glioma stem cells (GSCs) were crucial for glioma malignancy and accelerated tumor migration and invasion. The migration and invasion of malignant glioma cells into the surrounding normal brain tissues cause the poor outcome. miR-145, a miRNA found to be expressed in neurons, was recently found to have reduced expression in glioblastoma multiforme tumors. And miR-145 loss in glioma cells led to increased cell proliferation and invasion. However, its function on the migration and invasion of GSCs was still unknown. In this study, we aimed to identify the effects and mechanisms of miR-145 on the migration and invasion of GSCs. Our investigations revealed that miR-145 was low expressed in malignant glioma tissues and their corresponding GSCs. Knockdown of miR-145 in vitro could enhance the migration and invasion of GSCs, while up-regulation of miR-145 had the opposite effects. Further investigation of the potential mechanism demonstrated that the function of miR-145 in regulating the migration and invasion of GSCs is mediated by its targeting of ABCG2 mRNA. ABCG2 is an ATP-binding cassette transporter protein, which was identified to be overexpressed in GSCs and higher-grade glioma tissues. We found that miR-145 was negative correlated with ABCG2 levels in GSCs, and reduction in ABCG2 expression decreased the cell migration and invasion of GSCs. Further, a luciferase reporter proved that ABCG2 was a direct target of miR-145 in GSCs. Thus, these findings underscore the potential of miR-145 to regulate the migration and invasion of GSCs through targeting ABCG2.

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  • Adammek, M., Greve, B., Kässens, N., Schneider, C., Brüggemann, K., Schüring, A.N., et al. (2013) MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of an in vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors. Fertility and sterility 99(5), 1346–1355.e5.

  • Alison, M. R., Islam, S., & Wright, N. A. (2010). Stem cells in cancer: Instigators and propagators? Journal of Cell Science, 123(Pt 14), 2357–2368.

    CAS  PubMed  Article  Google Scholar 

  • Bao, S., Wu, Q., McLendon, R. E., Hao, Y., Shi, Q., Hjelmeland, A. B., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444, 756–760.

    CAS  PubMed  Article  Google Scholar 

  • Beier, D., Röhrl, S., Pillai, D. R., Schwarz, S., Kunz-Schughart, L. A., Leukel, P., et al. (2008). Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Research, 68(14), 5706–5715.

    CAS  PubMed  Article  Google Scholar 

  • Bhatia, P., Bernier, M., Sanghvi, M., Moaddel, R., Schwarting, R., Ramamoorthy, A., et al. (2012). Breast cancer resistance protein (BCRP/ABCG2) localises to the nucleus in glioblastoma multiforme cells. Xenobiotica, 42(8), 748–755.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Bise, R., Kanade, T., Yin, Z., & Huh, S. I. (2011). Automatic cell tracking applied to analysis of cell migration in wound healing assay. IEEE Conference Proceedings of Engineering in Medicine Biology Society, 2011, 6174–6179.

    Google Scholar 

  • Bleau, A. M., Hambardzumyan, D., Ozawa, T., Fomchenko, E. I., Huse, J. T., Brennan, C. W., et al. (2009). PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell, 4(3), 226–235.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Campayo, M., Navarro, A., Viñolas, N., Diaz, T., Tejero, R., Gimferrer, J. M., et al. (2013). Low miR-145 and high miR-367 are associated with unfavourable prognosis in resected nonsmall cell lung cancer. European Respiratory Journal, 41(5), 1172–1178.

    CAS  PubMed  Article  Google Scholar 

  • Chen, Z., Liu, F., Ren, Q., Zhao, Q., Ren, H., Lu, S., et al. (2010). Suppression of ABCG2 inhibits cancer cell proliferation. International Journal of Cancer, 126(4), 841–851.

    CAS  Google Scholar 

  • Chiou, S. H., Yu, C. C., Huang, C. Y., Lin, S. C., Liu, C. J., Tsai, T. H., et al. (2008). Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clinical Cancer Research, 14, 4085–4095.

    CAS  PubMed  Article  Google Scholar 

  • Darling, J. L. (1990). The in vitro biology of human brain tumors. In D. G. T. Thomas (Ed.), Neuro-oncology: Primary malignant brain tumors (pp. 1–25). Baltimore Md: Johns Hopkins University Press.

    Google Scholar 

  • Fillmore, H. L., VanMeter, T. E., & Broaddus, W. C. (2001). Membrane-type matrix metalloproteinases (MT-MMPs): Expression and function during glioma invasion. Journal of Neuro-oncology, 53(2), 187–202.

    CAS  PubMed  Article  Google Scholar 

  • Haapa-Paananen, S., Chen, P., Hellström, K., Kohonen, P., Hautaniemi, S., Kallioniemi, O., et al. (2013). Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation. PLoS One, 8(4), e60930.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Ho, M. M., Ng, A. V., Lam, S., & Hung, J. Y. (2007). Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research, 67, 4827–4833.

    CAS  PubMed  Article  Google Scholar 

  • Jia, J., Tian, Q., Ling, S., Liu, Y., Yang, S., & Shao, Z. (2013). miR-145 suppresses osteogenic differentiation by targeting Sp7. FEBS Letters, 587(18), 3027–3031.

    CAS  PubMed  Article  Google Scholar 

  • Jin, Y., Bin, Z. Q., Qiang, H., Liang, C., Hua, C., Jun, D., et al. (2009). ABCG2 is related with the grade of glioma and resistance to mitoxantrone, a chemotherapeutic drug for glioma. Journal of Cancer Research and Clinical Oncology, 135(10), 1369–1376.

    CAS  PubMed  Article  Google Scholar 

  • Lee, H. K., Bier, A., Cazacu, S., Finniss, S., Xiang, C., Twito, H., et al. (2013). MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor. PLoS One, 8(2), e54652.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 120(1), 15–20.

    CAS  PubMed  Article  Google Scholar 

  • Li, W. Q., Li, Y. M., Tao, B. B., Lu, Y. C., Hu, G. H., Liu, H. M., et al. (2010). Downregulation of ABCG2 expression in glioblastoma cancer stem cells with miRNA-328 may decrease their chemoresistance. Medical Science Monitor, 16(10), HY27–HY30.

    PubMed  Google Scholar 

  • Lu, Y., Chopp, M., Zheng, X., Katakowski, M., Buller, B., & Jiang, F. (2013). MiR-145 reduces ADAM17 expression and inhibits in vitro migration and invasion of glioma cells. Oncology Reports, 29(1), 67–72.

    PubMed Central  PubMed  Google Scholar 

  • Mohan, A., Kandalam, M., Ramkumar, H. L., Gopal, L., & Krishnakumar, S. (2006). Stem cell markers: ABCG2 and MCM2 expression in retinoblastoma. British Journal of Ophthalmology, 90, 889–893.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Okamoto, A., Chikamatsu, K., Sakakura, K., Hatsushika, K., Takahashi, G., & Masuyama, K. (2009). Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncology, 45, 633–639.

    CAS  PubMed  Article  Google Scholar 

  • Omran, O. M. (2012). The prognostic value of breast cancer resistance protein (BCRB/ABCG2) expression in breast carcinomas. Journal of Environmental Pathology, Toxicology and Oncology, 31(4), 367–376.

    PubMed  Article  Google Scholar 

  • Pek, J. W., Lim, A. K., & Kai, T. (2009). Drosophila maelstrom ensures proper germline stem cell lineage differentiation by repressing microRNA-7. Developmental Cell, 17, 417–424.

    CAS  PubMed  Article  Google Scholar 

  • Rani, S. B., Rathod, S. S., Karthik, S., Kaur, N., Muzumdar, D., & Shiras, A. S. (2013). MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro Oncology, 15(10), 1302–1316.

    CAS  PubMed  Article  Google Scholar 

  • Shi, L., Wan, Y., Sun, G., Gu, X., Qian, C., Yan, W., et al. (2012). Functional differences of miR-125b on the invasion of primary glioblastoma CD133-negative cells and CD133-positive cells. NeuroMolecular Medicine, 14(4), 303–316.

    CAS  PubMed  Article  Google Scholar 

  • Speranza, M. C., Frattini, V., Pisati, F., Kapetis, D., Porrati, P., Eoli, M., et al. (2012). NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma. Oncotarget, 3(7), 723–734.

    PubMed Central  PubMed  Google Scholar 

  • Stupp, R., Tonn, J. C., Brada, M., & Pentheroudakis, G. (2010). High-grade malignant glioma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 21, v190–v193.

    PubMed  Article  Google Scholar 

  • Wang, F., Xue, X., Wei, J., An, Y., Yao, J., Cai, H., et al. (2010). hsa-miR-520h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations. British Journal of Cancer, 103(4), 567–574.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Xia, H., Cheung, W. K., Ng, S. S., Jiang, X., Jiang, S., Sze, J., et al. (2012). Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. Journal of Biological Chemistry, 287(13), 9962–9971.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Xiang, L., Su, P., Xia, S., Liu, Z., Wang, Y., Gao, P., et al. (2011). ABCG2 is associated with HER-2 expression, lymph node metastasis and clinical stage in breast invasive ductal carcinoma. Diagnostic Pathology, 6, 90.

    PubMed Central  PubMed  Article  Google Scholar 

  • Xu, Q., Liu, L., Qian, X., Chen, Q., Jiang, Y., Li, D., et al. (2012). MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Research, 40, 761–774.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Xu, Z. Y., Wang, K., Li, X. Q., Chen, S., Deng, J. M., Cheng, Y., et al. (2013). The ABCG2 transporter is a key molecular determinant of the efficacy of sonodynamic therapy with Photofrin in glioma stem-like cells. Ultrasonics, 53(1), 232–238.

    CAS  PubMed  Article  Google Scholar 

  • Yang, S., Cui, H., Xie, N., Icyuz, M., Banerjee, S., Antony, V. B., et al. (2013). miR-145 regulates myofibroblast differentiation and lung fibrosis. FASEB Journal, 27(6), 2382–2391.

    CAS  PubMed  Article  Google Scholar 

  • Ye, X. Z., Xu, S. L., Xin, Y. H., Yu, S. C., Ping, Y. F., Chen, L., et al. (2012). Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. Journal of Immunology, 189(1), 444–453.

    CAS  Article  Google Scholar 

  • Zhou, S., Schuetz, J. D., Bunting, K. D., Colapietro, A. M., Sampath, J., Morris, J. J., et al. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Medicine, 7(9), 1028–1034.

    CAS  PubMed  Article  Google Scholar 

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This work was supported by the China Natural Science Foundation (81000963, 81370062, and 81302196), Jiangsu Province’s 333 Talent Program (BRA2011046), Jiangsu Province “six personnel peak” funded projects (2013-WSN-028), Jiangsu Province’s Natural Science Foundation (BK2012670), Medical Research Foundation by Jiangsu Province Health Department (YG201301 and Z201318), the Clinical Technology Development of Jiangsu University (JLY20120053), the Kunshan Social Development Foundation (KS1006, KS1009), and the Suzhou Social Development Foundation (SYS201063). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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All authors have declared the sources of research funding for this manuscript and have no financial or other contractual agreements that might cause (or be perceived as causes of) conflicts of interest.

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Correspondence to Lei Shi or Xingli Fu.

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Lei Shi, Zhimin Wang, Guan Sun, Yi Wan, and Jun Guo have contributed equally to this work.

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Shi, L., Wang, Z., Sun, G. et al. miR-145 Inhibits Migration and Invasion of Glioma Stem Cells by Targeting ABCG2. Neuromol Med 16, 517–528 (2014).

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  • miR-145
  • Migration
  • Invasion
  • Glioma stem cells
  • ABCG2