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MiR-34a deficiency accelerates medulloblastoma formation in vivo

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MiR-34a deficiency accelerates medulloblastoma formation in vivo. / Thor, Theresa; Künkele, Annette; Pajtler, Kristian W; Wefers, Annika K; Stephan, Harald; Mestdagh, Pieter; Heukamp, Lukas C; Hartmann, Wolfgang; Vandesompele, Jo; Sadowski, Natalie; Becker, Lore; Garrett, Lillian; Hölter, Sabine M; Horsch, Marion; Calzada-Wack, Julia; Klein-Rodewald, Tanja; Racz, Ildiko; Zimmer, Andreas; Beckers, Johannes; Neff, Frauke; Klopstock, Thomas; De Antonellis, Pasqualino; Zollo, Massimo; Wurst, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valérie; Schüller, Ulrich; Angelis, Martin Hrabě de; Eggert, Angelika; Schramm, Alexander; Schulte, Johannes H.

In: INT J CANCER, Vol. 136, No. 10, 15.05.2015, p. 2293-303.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Thor, T, Künkele, A, Pajtler, KW, Wefers, AK, Stephan, H, Mestdagh, P, Heukamp, LC, Hartmann, W, Vandesompele, J, Sadowski, N, Becker, L, Garrett, L, Hölter, SM, Horsch, M, Calzada-Wack, J, Klein-Rodewald, T, Racz, I, Zimmer, A, Beckers, J, Neff, F, Klopstock, T, De Antonellis, P, Zollo, M, Wurst, W, Fuchs, H, Gailus-Durner, V, Schüller, U, Angelis, MHD, Eggert, A, Schramm, A & Schulte, JH 2015, 'MiR-34a deficiency accelerates medulloblastoma formation in vivo', INT J CANCER, vol. 136, no. 10, pp. 2293-303. https://doi.org/10.1002/ijc.29294

APA

Thor, T., Künkele, A., Pajtler, K. W., Wefers, A. K., Stephan, H., Mestdagh, P., Heukamp, L. C., Hartmann, W., Vandesompele, J., Sadowski, N., Becker, L., Garrett, L., Hölter, S. M., Horsch, M., Calzada-Wack, J., Klein-Rodewald, T., Racz, I., Zimmer, A., Beckers, J., ... Schulte, J. H. (2015). MiR-34a deficiency accelerates medulloblastoma formation in vivo. INT J CANCER, 136(10), 2293-303. https://doi.org/10.1002/ijc.29294

Vancouver

Thor T, Künkele A, Pajtler KW, Wefers AK, Stephan H, Mestdagh P et al. MiR-34a deficiency accelerates medulloblastoma formation in vivo. INT J CANCER. 2015 May 15;136(10):2293-303. https://doi.org/10.1002/ijc.29294

Bibtex

@article{66f25b669a0b4e8291ff12e6afb7f1d3,
title = "MiR-34a deficiency accelerates medulloblastoma formation in vivo",
abstract = "Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.",
keywords = "Animals, Cell Line, Tumor, Cell Proliferation, Cerebellar Neoplasms, Cerebellum, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Medulloblastoma, Mice, Mice, Transgenic, MicroRNAs, Phenotype, Signal Transduction, Journal Article, Research Support, Non-U.S. Gov't",
author = "Theresa Thor and Annette K{\"u}nkele and Pajtler, {Kristian W} and Wefers, {Annika K} and Harald Stephan and Pieter Mestdagh and Heukamp, {Lukas C} and Wolfgang Hartmann and Jo Vandesompele and Natalie Sadowski and Lore Becker and Lillian Garrett and H{\"o}lter, {Sabine M} and Marion Horsch and Julia Calzada-Wack and Tanja Klein-Rodewald and Ildiko Racz and Andreas Zimmer and Johannes Beckers and Frauke Neff and Thomas Klopstock and {De Antonellis}, Pasqualino and Massimo Zollo and Wolfgang Wurst and Helmut Fuchs and Val{\'e}rie Gailus-Durner and Ulrich Sch{\"u}ller and Angelis, {Martin Hrab{\v e} de} and Angelika Eggert and Alexander Schramm and Schulte, {Johannes H}",
note = "{\textcopyright} 2014 UICC.",
year = "2015",
month = may,
day = "15",
doi = "10.1002/ijc.29294",
language = "English",
volume = "136",
pages = "2293--303",
journal = "INT J CANCER",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "10",

}

RIS

TY - JOUR

T1 - MiR-34a deficiency accelerates medulloblastoma formation in vivo

AU - Thor, Theresa

AU - Künkele, Annette

AU - Pajtler, Kristian W

AU - Wefers, Annika K

AU - Stephan, Harald

AU - Mestdagh, Pieter

AU - Heukamp, Lukas C

AU - Hartmann, Wolfgang

AU - Vandesompele, Jo

AU - Sadowski, Natalie

AU - Becker, Lore

AU - Garrett, Lillian

AU - Hölter, Sabine M

AU - Horsch, Marion

AU - Calzada-Wack, Julia

AU - Klein-Rodewald, Tanja

AU - Racz, Ildiko

AU - Zimmer, Andreas

AU - Beckers, Johannes

AU - Neff, Frauke

AU - Klopstock, Thomas

AU - De Antonellis, Pasqualino

AU - Zollo, Massimo

AU - Wurst, Wolfgang

AU - Fuchs, Helmut

AU - Gailus-Durner, Valérie

AU - Schüller, Ulrich

AU - Angelis, Martin Hrabě de

AU - Eggert, Angelika

AU - Schramm, Alexander

AU - Schulte, Johannes H

N1 - © 2014 UICC.

PY - 2015/5/15

Y1 - 2015/5/15

N2 - Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.

AB - Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cerebellar Neoplasms

KW - Cerebellum

KW - Gene Expression Regulation, Neoplastic

KW - Gene Knockout Techniques

KW - Humans

KW - Medulloblastoma

KW - Mice

KW - Mice, Transgenic

KW - MicroRNAs

KW - Phenotype

KW - Signal Transduction

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/ijc.29294

DO - 10.1002/ijc.29294

M3 - SCORING: Journal article

C2 - 25348795

VL - 136

SP - 2293

EP - 2303

JO - INT J CANCER

JF - INT J CANCER

SN - 0020-7136

IS - 10

ER -