MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma(442 views) Garzia L, Andolfo I, Cusanelli E, Marino N, Petrosino G, De Martino D, Esposito V, Galeone A, Navas L, Esposito S, Gargiulo S, Fattet S, Donofrio V, Cinalli G, Brunetti A, Del Vecchio L, Northcott PA, Delattre O, Taylor MD, Iolascon A, Zollo M
Plosone (ISSN: 1932-6203, 1932-6203electronic, 1932-6203linking), 2009 Mar 24; 4(3): e4998-e4998.
CEINGE, Centro di Ingegneria Genetica e Biotecnologia Avanzate, Naples, Italy
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Naples, Italy
Dip. di Scienze Cliniche Veterinarie - Sez. di Clinica Chirurgica, Università di Napoli Federico II, Naples, Italy
Diagnostic Imaging Department, University of Naples Federico II, IBB-CNR, Naples, Italy
Unité de Génétique et Biologie des Cancers, Institut Curie, Paris, France
Anatomia Patologica Ospedale Pausilipon - AORN Santobono-Pausilipon, Naples, Italy
Pediatric Neurosurgery, Santobono-Pausilipon Children's Hospital, Naples, Italy
Department of Biomorphological and Functional Sciences, Institute of Biostructures and Bioimages of the National Research Council, University Federico II, Naples, Italy
DBBM, Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Ontario, ON, Canada
Facoltà di Scienze Biotecnologiche, Università di Napoli Federico II, Naples, Italy
References: Bartel, D.P., (2004) MicroRNAs: Genomics, biogenesis, mechanism, and function, 116, pp. 281-297. , Cel
Hammond, S.M., MicroRNAs as oncogenes (2006) Curr Opin Genet Dev, 16, pp. 4-9
Calin, G.A., Dumitru, C.D., Shimizu, M., Bichi, R., Zupo, S., Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia (2002) Proc Natl Acad Sci U S A, 99, pp. 15524-15529
Ciafre, S.A., Galardi, S., Mangiola, A., Ferracin, M., Liu, C.G., Extensive modulation of a set of microRNAs in primary glioblastoma (2005) Biochem Biophys Res Commun, 334, pp. 1351-1358
Michael, M.Z., OC, S.M., van Holst Pellekaan, N.G., Young, G.P., James, R.J., Reduced accumulation of specific microRNAs in colorectal neoplasia (2003) Mol Cancer Res, 1, pp. 882-891
Fabbri, M., Garzon, R., Cimmino, A., Liu, Z., Zanesi, N., MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B (2007) Proc Natl Acad Sci U S A, 104, pp. 15805-15810
Ma, L., Teruya-Feldstein, J., Weinberg, R.A., Tumour invasion and metastasis initiated by microRNA-10b in breast cancer (2007) Nature, 449, pp. 682-688
Gilbertson, R.J., Ellison, D.W., The origins of medulloblastoma subtypes (2008) Annu Rev Pathol, 3, pp. 341-365
Buhren, J., Christoph, A.H., Buslei, R., Albrecht, S., Wiestler, O.D., Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features: Evidence for a medulloblastoma subtype derived from the external granule cell layer (2000) J Neuropathol Exp Neurol, 59, pp. 229-240
Katsetos, C.D., Krishna, L., Frankfurter, A., Karkavelas, G., Wolfe, D.E., A cytomorphological scheme of differentiating neuronal phenotypes in cerebellar medulloblastomas based on immunolocalization of class III beta-tubulin isotype (beta III) and proliferating cell nuclear antigen (PCNA)/cyclin (1995) Clin Neuropathol, 14, pp. 72-81
Marino, S., Medulloblastoma: Developmental mechanisms out of control (2005) Trends Mol Med, 11, pp. 17-22
Yang, S.Y., Wang, K.C., Cho, B.K., Kim, Y.Y., Lim, S.Y., Radiation-induced cerebellar glioblastoma at the site of a treated medulloblastoma: Case report (2005) J Neurosurg, 102, pp. 417-422
Patrice, S.J., Tarbell, N.J., Goumnerova, L.C., Shrieve, D.C., Black, P.M., Results of radiosurgery in the management of recurrent and residual medulloblastoma (1995) Pediatr Neurosurg, 22, pp. 197-203
Kombogiorgas, D., Sgouros, S., Walsh, A.R., Hockley, A.D., Stevens, M., Outcome of children with posterior fossa medulloblastoma: A single institution experience over the decade 1994-2003 (2007) Childs Nerv Syst, 23, pp. 399-405
Huntly, B.J., Gilliland, D.G., Cancer biology: Summing up cancer stem cells (2005) Nature, 435, pp. 1169-1170
Singh, S.K., Clarke, I.D., Hide, T., Dirks, P.B., Cancer stem cells in nervous system tumors (2004) Oncogene, 23, pp. 7267-7273
Yang, Z.J., Ellis, T., Markant, S.L., Read, T.A., Kessler, J.D., Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells (2008) Cancer Cell, 14, pp. 135-145
Solecki, D.J., Liu, X.L., Tomoda, T., Fang, Y., Hatten, M.E., Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation (2001) Neuron, 31, pp. 557-568
Ishibashi, M., Moriyoshi, K., Sasai, Y., Shiota, K., Nakanishi, S., Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system (1994) Embo J, 13, pp. 1799-1805
Ishibashi, M., Ang, S.L., Shiota, K., Nakanishi, S., Kageyama, R., Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects (1995) Genes Dev, 9, pp. 3136-3148
Nakamura, Y., Sakakibara, S., Miyata, T., Ogawa, M., Shimazaki, T., The bHLH gene hes1 as a repressor of the neuronal commitment of CNS stem cells (2000) J Neurosci, 20, pp. 283-293
Fan, X., Mikolaenko, I., Elhassan, I., Ni, X., Wang, Y., Notch1 and notch2 have opposite effects on embryonal brain tumor growth (2004) Cancer Res, 64, pp. 7787-7793
Hallahan, A.R., Pritchard, J.I., Hansen, S., Benson, M., Stoeck, J., The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas (2004) Cancer Res, 64, pp. 7794-7800
Leung, C., Lingbeek, M., Shakhova, O., Liu, J., Tanger, E., Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas (2004) Nature, 428, pp. 337-341
Griffiths-Jones, S., The microRNA Registry (2004) Nucleic Acids Res, 32, pp. D109-D111
Yanaihara, N., Caplen, N., Bowman, E., Seike, M., Kumamoto, K., Unique microRNA molecular profiles in lung cancer diagnosis and prognosis (2006) Cancer Cell, 9, pp. 189-198
Sandberg, A.A., Cytogenetics and molecular genetics of bladder cancer: A personal view (2002) Am J Med Genet, 115, pp. 173-182
Gramantieri, L., Ferracin, M., Fornari, F., Veronese, A., Sabbioni, S., Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma (2007) Cancer Res, 67, pp. 6092-6099
Jiang, J., Gusev, Y., Aderca, I., Mettler, T.A., Nagorney, D.M., Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival (2008) Clin Cancer Res, 14, pp. 419-427
Murakami, Y., Yasuda, T., Saigo, K., Urashima, T., Toyoda, H., Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues (2006) Oncogene, 25, pp. 2537-2545
Izant, J.G., McIntosh, J.R., Microtubule-associated proteins: A monoclonal antibody to MAP2 binds to differentiated neurons (1980) Proc Natl Acad Sci U S A, 77, pp. 4741-4745
Li, X.N., Parikh, S., Shu, Q., Jung, H.L., Chow, C.W., Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells (2004) Clin Cancer Res, 10, pp. 1150-1159
Hatakeyama, J., Bessho, Y., Katoh, K., Ookawara, S., Fujioka, M., Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation (2004) Development, 131, pp. 5539-5550
Fan, X., Matsui, W., Khaki, L., Stearns, D., Chun, J., Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors (2006) Cancer Res, 66, pp. 7445-7452
Kondo, T., Setoguchi, T., Taga, T., Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line (2004) Proc Natl Acad Sci U S A, 101, pp. 781-786
Goodell, M.A., Brose, K., Paradis, G., Conner, A.S., Mulligan, R.C., Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo (1996) J Exp Med, 183, pp. 1797-1806
Singh, S.K., Hawkins, C., Clarke, I.D., Squire, J.A., Bayani, J., Identification of human brain tumour initiating cells (2004) Nature, 432, pp. 396-401
Eberhart, C.G., In search of the medulloblast: Neural stem cells and embryonal brain tumors (2007) Neurosurg Clin N Am, 18, pp. 59-69. , viii-ix
Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U., Segal, E., The role of site accessibility in microRNA target recognition (2007) Nat Genet, 39, pp. 1278-1284
Kim, S., Lee, U.J., Kim, M.N., Lee, E.J., Kim, J.Y., MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2) (2008) J Biol Chem, 283, pp. 18158-18166
Pogoriler, J., Millen, K., Utset, M., Du, W., Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation (2006) Development, 133, pp. 3929-3937
Gilbertson, R.J., Clifford, S.C., PDGFRB is overexpressed in metastatic medulloblastoma (2003) Nat Genet, 35, pp. 197-198
MacDonald, T.J., Brown, K.M., LaFleur, B., Peterson, K., Lawlor, C., Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease (2001) Nat Genet, 29, pp. 143-152
Hatton, B.A., Villavicencio, E.H., Tsuchiya, K.D., Pritchard, J.I., Ditzler, S., The Smo/Smo model: Hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread (2008) Cancer Res, 68, pp. 1768-1776
Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., Glioma stem cells promote radioresistance by preferential activation of the DNA damage response (2006) Nature, 444, pp. 756-760
Blazek, E.R., Foutch, J.L., Maki, G., Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia (2007) Int J Radiat Oncol Biol Phys, 67, pp. 1-5
Ben-Porath, I., Thomson, M.W., Carey, V.J., Ge, R., Bell, G.W., An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors (2008) Nat Genet, 40, pp. 499-507
Gao, J.X., Cancer stem cells: The lessons from pre-cancerous stem cells (2008) J Cell Mol Med, 12, pp. 67-96
Grill, J., Dufour, C., Kalifa, C., High-dose chemotherapy in children with newly-diagnosed medulloblastoma (2006) Lancet Oncol, 7, pp. 787-789
Grill, J., Sainte-Rose, C., Jouvet, A., Gentet, J.C., Lejars, O., Treatment of medulloblastoma with postoperative chemotherapy alone: An SFOP prospective trial in young children (2005) Lancet Oncol, 6, pp. 573-580
Zimmermann, T.S., Lee, A.C., Akinc, A., Bramlage, B., Bumcrot, D., RNAi-mediated gene silencing in non-human primates (2006) Nature, 441, pp. 111-114
Schabet, M., Martos, J., Buchholz, R., Pietsch, T., Animal model of human medulloblastoma: Clinical, magnetic resonance imaging, and histopathological findings after intra-cisternal injection of MHH-MED-1 cells into nude rats (1997) Med Pediatr Oncol, 29, pp. 92-97
Bartel, D. P., (2004) MicroRNAs: Genomics, biogenesis, mechanism, and function, 116, pp. 281-297. , Cel
Hammond, S. M., MicroRNAs as oncogenes (2006) Curr Opin Genet Dev, 16, pp. 4-9
O'Donnell, K. A., Wentzel, E. A., Zeller, K. I., Dang, C. V., Mendell, J. T., c-Myc-regulated microRNAs modulate E2F1 expression (2005) Nature, 435, pp. 839-843
Calin, G. A., Dumitru, C. D., Shimizu, M., Bichi, R., Zupo, S., Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia (2002) Proc Natl Acad Sci U S A, 99, pp. 15524-15529
Ciafre, S. A., Galardi, S., Mangiola, A., Ferracin, M., Liu, C. G., Extensive modulation of a set of microRNAs in primary glioblastoma (2005) Biochem Biophys Res Commun, 334, pp. 1351-1358
Michael, M. Z., OC, S. M., van Holst Pellekaan, N. G., Young, G. P., James, R. J., Reduced accumulation of specific microRNAs in colorectal neoplasia (2003) Mol Cancer Res, 1, pp. 882-891
Gilbertson, R. J., Ellison, D. W., The origins of medulloblastoma subtypes (2008) Annu Rev Pathol, 3, pp. 341-365
Katsetos, C. D., Krishna, L., Frankfurter, A., Karkavelas, G., Wolfe, D. E., A cytomorphological scheme of differentiating neuronal phenotypes in cerebellar medulloblastomas based on immunolocalization of class III beta-tubulin isotype (beta III) and proliferating cell nuclear antigen (PCNA) /cyclin (1995) Clin Neuropathol, 14, pp. 72-81
MacDonald, T. J., Aggressive infantile embryonal tumors (2008) J Child Neurol, 23, pp. 1195-1204
Yang, S. Y., Wang, K. C., Cho, B. K., Kim, Y. Y., Lim, S. Y., Radiation-induced cerebellar glioblastoma at the site of a treated medulloblastoma: Case report (2005) J Neurosurg, 102, pp. 417-422
Patrice, S. J., Tarbell, N. J., Goumnerova, L. C., Shrieve, D. C., Black, P. M., Results of radiosurgery in the management of recurrent and residual medulloblastoma (1995) Pediatr Neurosurg, 22, pp. 197-203
Huntly, B. J., Gilliland, D. G., Cancer biology: Summing up cancer stem cells (2005) Nature, 435, pp. 1169-1170
Singh, S. K., Clarke, I. D., Hide, T., Dirks, P. B., Cancer stem cells in nervous system tumors (2004) Oncogene, 23, pp. 7267-7273
Yang, Z. J., Ellis, T., Markant, S. L., Read, T. A., Kessler, J. D., Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells (2008) Cancer Cell, 14, pp. 135-145
Solecki, D. J., Liu, X. L., Tomoda, T., Fang, Y., Hatten, M. E., Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation (2001) Neuron, 31, pp. 557-568
Hallahan, A. R., Pritchard, J. I., Hansen, S., Benson, M., Stoeck, J., The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas (2004) Cancer Res, 64, pp. 7794-7800
Sandberg, A. A., Cytogenetics and molecular genetics of bladder cancer: A personal view (2002) Am J Med Genet, 115, pp. 173-182
Izant, J. G., McIntosh, J. R., Microtubule-associated proteins: A monoclonal antibody to MAP2 binds to differentiated neurons (1980) Proc Natl Acad Sci U S A, 77, pp. 4741-4745
Li, X. N., Parikh, S., Shu, Q., Jung, H. L., Chow, C. W., Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells (2004) Clin Cancer Res, 10, pp. 1150-1159
Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., Mulligan, R. C., Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo (1996) J Exp Med, 183, pp. 1797-1806
Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Identification of human brain tumour initiating cells (2004) Nature, 432, pp. 396-401
Eberhart, C. G., In search of the medulloblast: Neural stem cells and embryonal brain tumors (2007) Neurosurg Clin N Am, 18, pp. 59-69. , viii-ix
Kim, S., Lee, U. J., Kim, M. N., Lee, E. J., Kim, J. Y., MicroRNA miR-199a* regulates the MET proto-oncogene and the downstream extracellular signal-regulated kinase 2 (ERK2) (2008) J Biol Chem, 283, pp. 18158-18166
MacDonald, T. J., Brown, K. M., LaFleur, B., Peterson, K., Lawlor, C., Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease (2001) Nat Genet, 29, pp. 143-152
Hatton, B. A., Villavicencio, E. H., Tsuchiya, K. D., Pritchard, J. I., Ditzler, S., The Smo/Smo model: Hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread (2008) Cancer Res, 68, pp. 1768-1776
Blazek, E. R., Foutch, J. L., Maki, G., Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia (2007) Int J Radiat Oncol Biol Phys, 67, pp. 1-5
Gao, J. X., Cancer stem cells: The lessons from pre-cancerous stem cells (2008) J Cell Mol Med, 12, pp. 67-96
Zimmermann, T. S., Lee, A. C., Akinc, A., Bramlage, B., Bumcrot, D., RNAi-mediated gene silencing in non-human primates (2006) Nature, 441, pp. 111-114
MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma
Background: Through negative regulation of gene expression, microRNAs (miRNAs) can function in cancers as oncosuppressors, and they can show altered expression in various tumor types. Here we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many cell-fate-determining stages. MBs occur bimodally, with the peak incidence seen between 3-4 years and 8-9 years of age, although it can also occur in adults. Notch regulates a subset of the MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulated these phenomena, and can be used in anti-cancer therapies. Methodology/Principal Findings: In a screening of MB cell lines, the miRNA miR-199b-5p was seen to be a regulator of the Notch pathway through its targeting of the transcription factor HES1. Down-regulation of HES1 expression by miR-199b-5p negatively regulates the proliferation rate and anchorage-independent growth of MB cells. MiR-199b-5p over-expression blocks expression of several cancer stem-cell genes, impairs the engrafting potential of MB cells in the cerebellum of athymic/nude mice, and of particular interest, decreases the MB stem-cell-like (CD133+) subpopulation of cells. In our analysis of 61 patients with MB, the expression of miR-199b-5p in the non-metastatic cases was significantly higher than in the metastatic cases (P = 0.001). Correlation with survival for these patients with high levels of miR-199b expression showed a positive trend to better overall survival than for the low-expressing patients. These data showing the down-regulation of miR-199b-5p in metastatic MBs suggest a potential silencing mechanism through epigenetic or genetic alterations. Upon induction of de-methylation using 5-aza-deoxycytidine, lower miR-199b-5p expression was seen in a panel of MB cell lines, supported an epigenetic mechanism of regulation. Furthermore, two cell lines (Med8a and UW228) showed significant upregulation of miR-199b-5p upon treatment. Infection with MB cells in an induced xenograft model in the mouse cerebellum and the use of an adenovirus carrying miR-199b-5p indicate a clinical benefit through this negative influence of miR-199b-5p on tumor growth and on the subset of MB stem-cell-like cells, providing further proof of concept. Conclusions/Significance: Despite advances in our understanding of the pathogenesis of MB, one-third of these patients remain incurable and current treatments can significantly damage long-term survivors. Here we show that miR-199b-5p expression correlates with metastasis spread, identifying a new molecular marker for a poor-risk class in patients with MB. We further show that in a xenograft model, MB tumor burden can be reduced, indicating the use of miR-199b-5p as an adjuvant therapy after surgery, in combination with radiation and chemotherapy, for the improvement of anti-cancer MB therapies and patient quality of life. To date, this is the first report that expression of a miRNA can deplete the tumor stem cells, indicating an interesting therapeutic approach for the targeting of these cells in brain tumors.
MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma
No results.
MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma