Abstract
MicroRNAs (miRNAs) are small noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell development, differentiation, and homeostasis. The total number and composition of miRNAs expressed per cell at different stages of development varies widely, and the same miRNA may function differently at different stages of development. In this prospective study, we evaluated the function of miR-125b at different developmental stages of glioblastoma cells, such as primary glioblastoma cells and the corresponding stem cells. CD133 is an important surface marker in glioblastoma stem cells. We found that the upregulation of miR-125b had no effects on the invasion of primary glioblastoma CD133-negative cells but that it could inhibit the invasion of corresponding CD133-positive cells; however, the downregulation of miR-125b also had no effects on the invasion of primary glioblastoma CD133-negative cells but promoted the invasion of CD133-positive cells. Further research into the underlying mechanism demonstrated that the effects of miR-125b on the invasion of glioblastoma CD133-positive cells were associated with the alteration of the expression of MMPs (MMP-2 and MMP-9) and corresponding inhibitors (RECK and TIMP3). Our results demonstrate that miR-125b expression plays an essential role in the invasion of glioblastoma CD133-positive cells but not CD133-negative cells. Therefore, miR-125b may represent a novel target for therapy targeting the invasion of glioblastoma stem cells in the future.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Blázquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., González-Feria, L., et al. (2008). Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Research, 68, 1945–1952.
Cairo, S., Wang, Y., de Reyniès, A., Duroure, K., Dahan, J., Redon, M., et al. (2010). Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. PNAS, 107, 20471–20476.
Cao, Y., Lathia, J. D., Eyler, C. E., Wu, Q., Li, Z., Wang, H., et al. (2010). Erythropoietin receptor signaling through stat3 is required for glioma stem cell maintenance. Genes & Cancer, 1, 50–61.
Chan, J. A., Krichevsky, A. M., & Kosik, K. S. (2005). MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Research, 65, 6029–6033.
Chen, C., Ridzon, D. A., Broomer, A. J., Zhou, Z., Lee, D. H., Nguyen, J. T., et al. (2005). Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Research, 33, e179.
Cheng, L., Wu, Q., Guryanova, O. A., Huang, Z., Huang, Q., Rich, J. N., et al. (2011). Elevated invasive potential of glioblastoma stem cells. Biochemical and Biophysical Research Communications, 406, 643–648.
Ciafre, S. A., Galardi, S., Mangiola, A., Ferracin, M., Liu, C. G., Sabatino, G., et al. (2005). Extensive modulation of a set of microRNAs in primary glioblastoma. Biochemical and Biophysical Research Communications, 334, 1351–1358.
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.
Gabriely, G., Wurdinger, T., Kesari, S., Esau, C. C., Burchard, J., Linsley, P. S., et al. (2008). MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Molecular and Cellular Biology, 28, 5369–5380.
Hatfield, S. D., Shcherbata, H. R., Fischer, K. A., Nakahara, K., Carthew, R. W., & Ruohola-Baker, H. (2005). Stem cell division is regulated by the microRNA pathway. Nature, 435, 974–978.
Johnson, S. M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., et al. (2005). RAS is regulated by the let-7 microRNA family. Cell, 120, 635–647.
Kassiri, Z., Oudit, G. Y., Kandalam, V., Awad, A., Wang, X., Ziou, X., et al. (2009). Loss of TIMP3 enhances interstitial nephritis and fibrosis. Journal of the American Society of Nephrology, 20, 1223–1235.
Kelly, P. N., Dakic, A., Adams, J. M., Nutt, S. L., & Strasser, A. (2007). Tumor growth need not be driven by rare cancer stem cells. Science, 317, 337.
Kuhn, D. E., Nuovo, G. J., Martin, M. M., Malana, G. E., Pleister, A. P., Jiang, J., et al. (2008). Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts. Biochemical and Biophysical Research Communications, 370, 473–477.
Lee, Y. S., Kim, H. K., Chung, S., Kim, K., & Dutta, A. (2005). Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. Journal of Biological Chemistry, 280, 16635–16641.
Liu, L. T., Chang, H. C., Chiang, L. C., & Hung, W. C. (2003). Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Research, 63, 3069–3072.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C(T)) Method. Methods, 25, 402–408.
Nakano, I., & Saya, H. (2010). Cancer stem cells in malignant glioma-the mechanism of cancer initiation and the therapeutic development. No Shinkei Geka, 38, 879–889.
Nelson, P. T., Baldwin, D. A., Kloosterman, W. P., Kauppinen, S., Plasterk, R. H. A., & Mourelatos, Z. (2005). RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain. RNA, 12, 187–191.
Pan, T. H., Wang, Y. Y., Zhang, S. G., Zhang, J. X., Li, R., Yan, W., et al. (2011). Research on the effects of PIAS3 expression on the invasion of glioma TJ905 cells. Zhonghua Wai Ke Za Zhi, 49, 440–444.
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.
Shi, L., Cheng, Z., Zhang, J., Li, R., Zhao, P., Fu, Z., et al. (2008). hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Research, 1236, 185–193.
Shi, L., Zhang, S., Feng, K., Wu, F., Wan, Y., Wang, Z., et al. (2012). MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis. International Journal of Oncology, 40, 119–129.
Shi, L., Zhang, J., Pan, T., Zhou, J., Gong, W., Liu, N., et al. (2010). MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation. Brain Research, 1312, 120–126.
Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., et al. (2004). Identification of human brain tumour initiating cells. Nature, 432, 396–401.
Smirnova, L., Gräfe, A., Seiler, A., Schumacher, S., Nitsch, R., & Wulczyn, F. G. (2005). Regulation of miRNA expression during neural cell specification. European Journal of Neuroscience, 21, 1469–1477.
Stupp, R., & Hegi, M. E. (2007). Targeting brain-tumor stem cells. Nature Biotechnology, 25, 193–194.
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.
Vescovi, A. L., Galli, R., & Reynolds, B. A. (2006). Brain tumour stem cells. Nature Reviews Cancer, 6, 425–436.
Vlashi, E., Lagadec, C., Vergnes, L., Matsutani, T., Masui, K., Poulou, M., et al. (2011). Metabolic state of glioma stem cells and nontumorigenic cells. PNAS, 108, 16062–16067.
Xia, H. F., He, T. Z., Liu, C. M., Cui, Y., Song, P. P., Jin, X. H., et al. (2009a). MiR-125b expression affects the proliferation and apoptosis of human glioma cells by targeting bmf. Cellular Physiology and Biochemistry, 23, 347–358.
Xia, H., Qi, Y., Ng, S. S., Chen, X., Li, D., Chen, S., et al. (2009b). microRNA-146b inhibits glioma cell migration and invasion by targeting MMPs. Brain Research, 1269, 158–165.
Zhang, D., Jing, Z., Qiu, B., Wu, A., & Wang, Y. (2011). Temozolomide decreases invasion of glioma stem cells by down-regulating TGF-β2. Oncology Reports, 26, 901–908.
Zwaka, T. P., & Thomson, J. A. (2005). Differentiation of human embryonic stem cells occurs through symmetric cell division. Stem Cells, 23, 146–149.
Acknowledgments
This work was supported by the China Natural Science Foundation (81000963, 81072078, and 30872657), Jiangsu Province’s 333 Talent Program (BRA2011046), Jiangsu Province’s Natural Science Foundation (BK2008475, 2009444 and 2010580), the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU, the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Kunshan Social Development Foundation (Grant Number: KS1006, KS1009), and the Suzhou Social Development Foundation (SYS201063).
Conflict of interest
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.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Lei Shi, Yi Wan, Guan Sun, Xiaoyan Gu, Chunfa Qian, Wei Yan, Shuguang Zhang, and Tianhong Pan contributed equally to this work.
Rights and permissions
About this article
Cite this article
Shi, L., Wan, Y., Sun, G. et al. Functional Differences of miR-125b on the Invasion of Primary Glioblastoma CD133-Negative Cells and CD133-Positive Cells. Neuromol Med 14, 303–316 (2012). https://doi.org/10.1007/s12017-012-8188-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-012-8188-8