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@ARTICLE{Vaillant:127681,
      author       = {C. Vaillant and P. Valdivieso and S. Nuciforo and M.
                      Kool$^*$ and A. Schwarzentruber-Schauerte and H. Méreau and
                      E. Cabuy and J. A. Lobrinus and S. Pfister$^*$ and A. Zuniga
                      and S. Frank and R. Zeller},
      title        = {{S}erpine2/{PN}-1 {I}s {R}equired for {P}roliferative
                      {E}xpansion of {P}re-{N}eoplastic {L}esions and {M}alignant
                      {P}rogression to {M}edulloblastoma.},
      journal      = {PLoS one},
      volume       = {10},
      number       = {4},
      issn         = {1932-6203},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DKFZ-2017-03704},
      pages        = {e0124870 -},
      year         = {2015},
      abstract     = {Medulloblastomas are malignant childhood brain tumors that
                      arise due to the aberrant activity of developmental pathways
                      during postnatal cerebellar development and in adult humans.
                      Transcriptome analysis has identified four major
                      medulloblastoma subgroups. One of them, the Sonic hedgehog
                      (SHH) subgroup, is caused by aberrant Hedgehog signal
                      transduction due to mutations in the Patched1 (PTCH1)
                      receptor or downstream effectors. Mice carrying a Patched-1
                      null allele (Ptch1∆/+) are a good model to study the
                      alterations underlying medulloblastoma development as a
                      consequence of aberrant Hedgehog pathway
                      activity.Transcriptome analysis of human medulloblastomas
                      shows that SERPINE2, also called Protease Nexin-1 (PN-1) is
                      overexpressed in most medulloblastomas, in particular in the
                      SHH and WNT subgroups. As siRNA-mediated lowering of
                      SERPINE2/PN-1 in human medulloblastoma DAOY cells reduces
                      cell proliferation, we analyzed its potential involvement in
                      medulloblastoma development using the Ptch1∆/+ mouse
                      model. In Ptch1∆/+ mice, medulloblastomas arise as a
                      consequence of aberrant Hedgehog pathway activity. Genetic
                      reduction of Serpine2/Pn-1 interferes with medulloblastoma
                      development in Ptch1∆/+ mice, as $~60\%$ of the
                      pre-neoplastic lesions (PNLs) fail to develop into
                      medulloblastomas and remain as small cerebellar nodules. In
                      particular the transcription factor Atoh1, whose expression
                      is essential for development of SHH subgroup
                      medulloblastomas is lost. Comparative molecular analysis
                      reveals the distinct nature of the PNLs in young
                      Ptch1∆/+Pn-1Δ/+ mice. The remaining wild-type Ptch1
                      allele escapes transcriptional silencing in most cases and
                      the aberrant Hedgehog pathway activity is normalized.
                      Furthermore, cell proliferation and the expression of the
                      cell-cycle regulators Mycn and Cdk6 are significantly
                      reduced in PNLs of Ptch1∆/+Pn-1Δ/+ mice.Our analysis
                      provides genetic evidence that aberrant Serpine2/Pn-1 is
                      required for proliferation of human and mouse
                      medulloblastoma cells. In summary, our analysis shows that
                      Serpine2/PN-1 boosts malignant progression of PNLs to
                      medulloblastomas, in which the Hedgehog pathway is activated
                      in a SHH ligand-independent manner.},
      keywords     = {Hedgehog Proteins (NLM Chemicals) / PTCH protein, human
                      (NLM Chemicals) / Patched Receptors (NLM Chemicals) /
                      Patched-1 Receptor (NLM Chemicals) / Ptch1 protein, mouse
                      (NLM Chemicals) / Receptors, Cell Surface (NLM Chemicals) /
                      Serpin E2 (NLM Chemicals) / Matrix Metalloproteinase 9 (NLM
                      Chemicals)},
      cin          = {B062},
      ddc          = {500},
      cid          = {I:(DE-He78)B062-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25901736},
      pmc          = {pmc:PMC4406471},
      doi          = {10.1371/journal.pone.0124870},
      url          = {https://inrepo02.dkfz.de/record/127681},
}