Genome‐wide transcriptome analyses reveal p53 inactivation mediated loss of miR‐34a expression in malignant peripheral nerve sheath tumours

Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive soft tissue tumours that occur either sporadically or in patients with neurofibromatosis type 1. The malignant transformation of the benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and these include genes involved in cell proliferation and genes implicated in tumour metastasis. In addition, a gene expression signature indicating p53 inactivation is seen in the majority of MPNSTs. Subsequent microRNA profiling of benign and malignant PNSTs indicated a relative down‐regulation of miR‐34a in most MPNSTs compared to neurofibromas. In vitro studies using the cell lines MPNST‐14 (NF1 mutant) and MPNST‐724 (from a non‐NF1 individual) show that exogenous expression of p53 or miR‐34a promotes apoptotic cell death. In addition, exogenous expression of p53 in MPNST cells induces miR‐34a and other miRNAs. Our data show that p53 inactivation and subsequent loss of expression of miR‐34a may significantly contribute to the MPNST development. Collectively, our findings suggest that deregulation of miRNAs has a potential role in the malignant transformation process in peripheral nerve sheath tumours. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  M. Pierotti,et al.  PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor. , 2009, Neuro-oncology.

[2]  P. Marynen,et al.  TP53 mutations are frequent in malignant NFI tumors , 1994, Genes, chromosomes & cancer.

[3]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[4]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[5]  R. West,et al.  Apo D in Soft Tissue Tumors: A Novel Marker for Dermatofibrosarcoma Protuberans , 2004, The American journal of surgical pathology.

[6]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[7]  D. Evans,et al.  Malignant peripheral nerve sheath tumours in neurofibromatosis 1 , 2002, Journal of medical genetics.

[8]  J Khan,et al.  The MYCN oncogene is a direct target of miR-34a , 2008, Oncogene.

[9]  S. Ramaswamy,et al.  Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis , 2004, Cell.

[10]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Lin He,et al.  The guardian's little helper: microRNAs in the p53 tumor suppressor network. , 2007, Cancer research.

[12]  Robert Tibshirani,et al.  Hybrid hierarchical clustering with applications to microarray data. , 2005, Biostatistics.

[13]  Franz M. Enzinger,et al.  Soft Tissue Tumors , 1983 .

[14]  I. Bièche,et al.  Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR , 2004, Molecular Cancer.

[15]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[16]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[17]  J. Uney,et al.  Twist-1 regulates the miR-199a/214 cluster during development , 2008, Nucleic acids research.

[18]  J. Declue,et al.  Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. , 2005, Cancer cell.

[19]  T O Nielsen,et al.  MicroRNA expression signature of human sarcomas , 2008, Oncogene.

[20]  Marc Ladanyi,et al.  TLE1 as a Diagnostic Immunohistochemical Marker for Synovial Sarcoma Emerging From Gene Expression Profiling Studies , 2007, The American journal of surgical pathology.

[21]  A. King,et al.  Malignant peripheral nerve sheath tumors in neurofibromatosis 1. , 2000, American journal of medical genetics.

[22]  C. Hartmann,et al.  Subclassification of Nerve Sheath Tumors by Gene Expression Profiling , 2004, Brain pathology.

[23]  D. Botstein,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[24]  G. Benvenuto,et al.  Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. , 2000, The Journal of clinical investigation.

[25]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[26]  Naoto Tsuchiya,et al.  Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells , 2007, Proceedings of the National Academy of Sciences.

[27]  M. Watson,et al.  Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. , 2006, Cancer research.

[28]  V. Tarasov,et al.  Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest , 2007, Cell cycle.

[29]  D. Gutmann,et al.  International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. , 2002, Cancer research.

[30]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[31]  J. Goldblum,et al.  Soft tissue tumors , 2002 .

[32]  D. Louis,et al.  Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation. , 1999, The American journal of pathology.

[33]  M. Watson,et al.  Gene Expression Profiling Reveals Unique Molecular Subtypes of Neurofibromatosis Type I‐associated and Sporadic Malignant Peripheral Nerve Sheath Tumors , 2004, Brain pathology.

[34]  G. Hutchins,et al.  Nf1-Dependent Tumors Require a Microenvironment Containing Nf1 +/−- and c-kit-Dependent Bone Marrow , 2008, Cell.

[35]  Michael A. Beer,et al.  Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. , 2007, Molecular cell.

[36]  Gavin D. Grant,et al.  Common markers of proliferation , 2006, Nature Reviews Cancer.

[37]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Moshe Oren,et al.  Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. , 2007, Molecular cell.

[39]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[40]  R. Plasterk,et al.  The diverse functions of microRNAs in animal development and disease. , 2006, Developmental cell.

[41]  Jeng-Shin Lee,et al.  Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Lowy,et al.  Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis , 1992, Cell.

[43]  C. Fletcher,et al.  Soft Tissue Tumors , 1995, Current Topics in Pathology.

[44]  R. Lothe,et al.  Topoisomerase-II alpha is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  Neil Sebire,et al.  A molecular map of mesenchymal tumors , 2005, Genome Biology.

[46]  R. Weinberg,et al.  Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis. , 2003, Cancer cell.

[47]  Akira Nakagawara,et al.  UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme. , 2003, Cancer research.

[48]  A. von Deimling,et al.  Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours. , 2004, European journal of cancer.

[49]  M. Ladanyi,et al.  SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. , 1998, The New England journal of medicine.

[50]  V. Rotter,et al.  Transcriptional programs following genetic alterations in p53, INK4A, and H-Ras genes along defined stages of malignant transformation. , 2005, Cancer research.

[51]  C. Ball,et al.  The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. , 2004, The American journal of pathology.

[52]  Jefferson Terry,et al.  Fluorescence In Situ Hybridization for the Detection of t(X;18)(p11.2;q11.2) in a Synovial Sarcoma Tissue Microarray Using a Breakapart-Style Probe , 2005, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[53]  R. Stallings,et al.  MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells , 2007, Oncogene.

[54]  Jin-Wu Nam,et al.  miR-29 miRNAs activate p53 by targeting p85α and CDC42 , 2009, Nature Structural &Molecular Biology.

[55]  Tsuyoshi Saito,et al.  DNA hypermethylation status of multiple genes in soft tissue sarcomas , 2006, Modern Pathology.

[56]  T. Jacks,et al.  NF1 Tumor Suppressor Gene Function Narrowing the GAP , 2001, Cell.