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

Abstract

BackgroundMedulloblastomas 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.ResultsTranscriptome 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-1 Δ/+ 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-1 Δ/+ mice.ConclusionsOur 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.

Expression pattern of human SERPINE2 in a variety of human tumors

“…The downregulation of SERPINE2 may activate the Erk1/2 and P38 signaling pathways and lead to an increased invasion and metastasis of glioma cells, in which SERPINE2 seems to play a pro-tumor role (24). In another study, however, SERPINE2 may mediate an anti-tumor activity as its deficiency leads to the reduced proliferation of medulloblastoma cells (25). Our tissue microarray shows that SERPINE2 is expressed differentially in different types of brain tumors: abundant in oligodendroglioma and glioblastoma and extremely low in atypical meningioma and malignant ependymoma (Fig.…”

“…Pagliara showed that SERPINE2 affects glioma cell migration and invasiveness through the regulation of uPA and MMP-9/2 expression levels, contributing to the degradation of the ECM during tumor invasion (24). However, another study showed that SERPINE2 promoted pre-neoplastic lesion progression to the medulloblastoma owing to aberrant Hedgehog pathway activity independent of the SHH ligand (25).…”

A unique gene expression signature is significantly differentially expressed in tumor-positive or tumor-negative sentinel lymph nodes in patients with melanoma

“…Serpin E2 (Protease Nexin-1 (PN-1), belongs to the Serpin protein superfamily and acts as a protease inhibitor mainly for thrombin, plasmin and plasminogen activators, all factors associated with tissue remodeling. Although theoretically its ability to reduce proteolysis and extracellular matrix degradation would protect against cancer cell invasion and metastasis, serpinE2 overexpression leads to upregulation of matrix-metalloproteinase MMP9 which cleaves serpinE2 to allow protease mediated remodeling [33] . SerpinE2 is highly upregulated upon MAPK pathway stimulation, its overexpression is common in many cancers with such pathway oncogenic alterations [33] .…”

“…Although theoretically its ability to reduce proteolysis and extracellular matrix degradation would protect against cancer cell invasion and metastasis, serpinE2 overexpression leads to upregulation of matrix-metalloproteinase MMP9 which cleaves serpinE2 to allow protease mediated remodeling [33] . SerpinE2 is highly upregulated upon MAPK pathway stimulation, its overexpression is common in many cancers with such pathway oncogenic alterations [33] . SOX10 is an essential factor for specification, survival and differentiation of neural crest derived lineages including melanocytes.…”

Serpin E2 promotes breast cancer metastasis by remodeling the tumor matrix and polarizing tumor associated macrophages

“…The extracellular serine protease inhibitor (serpin) serpinE2, also known as PN-1, is overexpressed in various human cancers, including breast [2] and plays an essential role in malignant progression and metastasis [2–4]. However, the mechanism by which serpinE2 promotes metastasis in breast cancer models remains largely unclear.…”