MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma

被引：51

作者：

Bai, Alfa H. C. ^{[1
]}

Milde, Till ^{[2
,3
]}

Remke, Marc ^{[1
,3
]}

Rolli, Claudio G. ^{[4
,5
]}

Hielscher, Thomas ^{[6
]}

Cho, Yoon-Jae ^{[7
]}

Kool, Marcel ^{[1
]}

Northcott, Paul A. ^{[8
]}

Jugold, Manfred ^{[9
]}

Bazhin, Alexandr V. ^{[10
]}

Eichmueller, Stefan B. ^{[11
]}

Kulozik, Andreas E. ^{[3
]}

Pscherer, Armin ^{[1
]}

Benner, Axel ^{[6
]}

Taylor, Michael D. ^{[8
]}

Pomeroy, Scott L. ^{[12
]}

Kemkemer, Ralf ^{[4
]}

Witt, Olaf ^{[2
,3
]}

Korshunov, Andrey ^{[13
,14
]}

Lichter, Peter ^{[1
]}

Pfister, Stefan M. ^{[1
,3
]}

机构：

[1] German Canc Res Ctr, Div Mol Genet B060, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol G340, D-69120 Heidelberg, Germany

[3] Univ Heidelberg, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[4] Max Planck Inst Intelligent Syst, Dept New Mat & Biosyst, Stuttgart, Germany

[5] Univ Heidelberg, Inst Phys Chem, Dept Biophys Chem, D-6900 Heidelberg, Germany

[6] German Canc Res Ctr, Div Biostat C060, D-69120 Heidelberg, Germany

[7] Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA

[8] Univ Toronto, Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada

[9] German Canc Res Ctr, Div Med Phys Radiol, D-69120 Heidelberg, Germany

[10] Univ Heidelberg, Dept Surg, D-6900 Heidelberg, Germany

[11] German Canc Res Ctr, Div Translat Immunol D015, D-69120 Heidelberg, Germany

[12] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[13] Univ Heidelberg, Dept Neuropathol, D-6900 Heidelberg, Germany

[14] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-6900 Heidelberg, Germany

来源：

ACTA NEUROPATHOLOGICA | 2012年 / 123卷 / 04期

关键词：

hsa-miR-182; Metastatic dissemination; SHH pathway; Medulloblastoma; PATHWAY; POLYCISTRON; PROFILES; SUBTYPES; CLUSTER; TUMOR;

D O I：

10.1007/s00401-011-0924-x

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.

引用

页码：529 / 538

页数：10

共 26 条

[1] Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome [J].

Cho, Yoon-Jae ;

Tsherniak, Aviad ;

Tamayo, Pablo ;

Santagata, Sandro ;

Ligon, Azra ;

Greulich, Heidi ;

Berhoukim, Rameen ;

Amani, Vladimir ;

Goumnerova, Liliana ;

Eberhart, Charles G. ;

Lau, Ching C. ;

Olson, James M. ;

Gilbertson, Richard J. ;

Gajjar, Amar ;

Delattre, Olivier ;

Kool, Marcel ;

Ligon, Keith ;

Meyerson, Matthew ;

Mesirov, Jill P. ;

Pomeroy, Scott L. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (11) :1424-1430

[2] Definition of Disease-Risk Stratification Groups in Childhood Medulloblastoma Using Combined Clinical, Pathologic, and Molecular Variables [J].

Ellison, David W. ;

Kocak, Mehmet ;

Dalton, James ;

Megahed, Hisham ;

Lusher, Meryl E. ;

Ryan, Sarra L. ;

Zhao, Wei ;

Nicholson, Sarah Leigh ;

Taylor, Roger E. ;

Bailey, Simon ;

Clifford, Steven C. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (11) :1400-1407

[3] Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor [J].

Fouladi, M ;

Gajjar, A ;

Boyett, JM ;

Walter, AW ;

Thompson, SJ ;

Merchant, TE ;

Jenkins, JJ ;

Langston, LW ;

Liu, AY ;

Kun, LE ;

Heideman, RL .

JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (10) :3234-3237

[4] Subtypes of medulloblastoma have distinct developmental origins [J].

Gibson, Paul ;

Tong, Yiai ;

Robinson, Giles ;

Thompson, Margaret C. ;

Currle, D. Spencer ;

Eden, Christopher ;

Kranenburg, Tanya A. ;

Hogg, Twala ;

Poppleton, Helen ;

Martin, Julie ;

Finkelstein, David ;

Pounds, Stanley ;

Weiss, Aaron ;

Patay, Zoltan ;

Scoggins, Matthew ;

Ogg, Robert ;

Pei, Yanxin ;

Yang, Zeng-Jie ;

Brun, Sonja ;

Lee, Youngsoo ;

Zindy, Frederique ;

Lindsey, Janet C. ;

Taketo, Makoto M. ;

Boop, Frederick A. ;

Sanford, Robert A. ;

Gajjar, Amar ;

Clifford, Steven C. ;

Roussel, Martine F. ;

McKinnon, Peter J. ;

Gutmann, David H. ;

Ellison, David W. ;

Wechsler-Reya, Robert ;

Gilbertson, Richard J. .

NATURE, 2010, 468 (7327) :1095-1099

[5] Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway [J].

Gokhale, Amit ;

Kunder, Ratika ;

Goel, Atul ;

Sarin, Rajiv ;

Moiyadi, Aliasgar ;

Shenoy, Asha ;

Mamidipally, Chandrasekhar ;

Noronha, Santosh ;

Kannan, Sadhana ;

Shirsat, Neelam Vishwanath .

JOURNAL OF CANCER RESEARCH AND THERAPEUTICS, 2010, 6 (04) :521-529

[6] Altered neural cell fates and medulloblastoma in mouse patched mutants [J].

Goodrich, LV ;

Milenkovic, L ;

Higgins, KM ;

Scott, MP .

SCIENCE, 1997, 277 (5329) :1109-1113

[7] An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice [J].

Gronych, Jan ;

Korshunov, Andrey ;

Bageritz, Josephine ;

Milde, Till ;

Jugold, Manfred ;

Hambardzumyan, Dolores ;

Remke, Marc ;

Hartmann, Christian ;

Witt, Hendrik ;

Jones, David T. W. ;

Witt, Olaf ;

Heiland, Sabine ;

Bendszus, Martin ;

Holland, Eric C. ;

Pfister, Stefan ;

Lichter, Peter .

JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (04) :1344-1348

[8] A microRNA polycistron as a potential human oncogene [J].

He, L ;

Thomson, JM ;

Hemann, MT ;

Hernando-Monge, E ;

Mu, D ;

Goodson, S ;

Powers, S ;

Cordon-Cardo, C ;

Lowe, SW ;

Hannon, GJ ;

Hammond, SM .

NATURE, 2005, 435 (7043) :828-833

[9]

HE XM, 1991, LAB INVEST, V64, P833

[10] Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features [J].

Kool, Marcel ;

Koster, Jan ;

Bunt, Jens ;

Hasselt, Nancy E. ;

Lakeman, Arjan ;

van Sluis, Peter ;

Troost, Dirk ;

Schouten-van Meeteren, Netteke ;

Caron, Huib N. ;

Cloos, Jacqueline ;

Mrsic, Alan ;

Ylstra, Bauke ;

Grajkowska, Wieslawa ;

Hartmann, Wolfgang ;

Pietsch, Torsten ;

Ellison, David ;

Clifford, Steven C. ;

Versteeg, Rogier .

PLOS ONE, 2008, 3 (08)

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