Serpine2/PN-1 Is Required for Proliferative Expansion of Pre-Neoplastic Lesions and Malignant Progression to Medulloblastoma

Abstract

<div><p>Background</p><p>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 <i>Patched1</i> (<i>PTCH1</i>) receptor or downstream effectors. Mice carrying a <i>Patched-1</i> null allele (<i>Ptch1</i>^∆/+) are a good model to study the alterations underlying medulloblastoma development as a consequence of aberrant Hedgehog pathway activity.</p><p>Results</p><p>Transcriptome analysis of human medulloblastomas shows that <i>SERPINE2</i>, also called <i>Protease Nexin-1</i> (<i>PN-1</i>) is overexpressed in most medulloblastomas, in particular in the SHH and WNT subgroups. As siRNA-mediated lowering of <i>SERPINE2/PN-1</i> in human medulloblastoma DAOY cells reduces cell proliferation, we analyzed its potential involvement in medulloblastoma development using the <i>Ptch1</i>^∆/+ mouse model. In <i>Ptch1</i>^∆/+ mice, medulloblastomas arise as a consequence of aberrant Hedgehog pathway activity. Genetic reduction of <i>Serpine2/Pn-1</i> interferes with medulloblastoma development in <i>Ptch1</i>^∆/+ 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 <i>Atoh1</i>, whose expression is essential for development of SHH subgroup medulloblastomas is lost. Comparative molecular analysis reveals the distinct nature of the PNLs in young <i>Ptch1</i>^∆/+<i>Pn-1</i>^Δ/+ mice. The remaining wild-type <i>Ptch1</i> 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 <i>Mycn</i> and <i>Cdk6</i> are significantly reduced in PNLs of <i>Ptch1</i>^∆/+<i>Pn-1</i>^Δ/+ mice.</p><p>Conclusions</p><p>Our analysis provides genetic evidence that aberrant <i>Serpine2/Pn-1</i> 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.</p></div