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Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma.

ABSTRACT: BACKGROUND:Treatment options of glioblastoma, the most aggressive primary brain tumor with frequent relapses and high mortality, are still very limited, urgently calling for novel therapeutic targets. Expression of the glycoprotein podoplanin correlates with poor prognosis in various cancer entities, including glioblastoma. Furthermore, podoplanin has been associated with tumor cell migration and proliferation in vitro; however, experimental data on its function in gliomagenesis in vivo are still missing. Hence, we have functionally investigated the impact of podoplanin on glioblastoma in a preclinical mouse model to evaluate its potential as a therapeutic target. METHODS:Fluorescence activated cell sorting, genome-wide expression analysis, and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9)-mediated deletion of podoplanin in patient-derived human glioblastoma cells were combined with organotypic brain slice cultures and intracranial injections into mice. RESULTS:We defined a malignant gene signature in tumor cells with high podoplanin expression. The increase and/or maintenance of high podoplanin expression in serial transplantations and in podoplaninlow-sorted glioblastoma cells during outgrowth indicated the association of high podoplanin expression and poor outcome. Unexpectedly, similar rates of proliferation, apoptosis, angiogenesis, and invasion were observed in control and podoplanin-deleted tumors. Accordingly, neither tumor growth nor survival was affected upon podoplanin loss. CONCLUSION:We report that tumor progression occurs independently of podoplanin. Thus, in contrast to previous suggestions, blocking of podoplanin does not represent a promising therapeutic approach. However, as podoplanin is associated with tumor aggressiveness and progression, we propose the cell surface protein as a biomarker for poor prognosis.

SUBMITTER: Eisemann T

PROVIDER: S-EPMC6380419 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma.

Eisemann Tanja T Costa Barbara B Harter Patrick N PN Wick Wolfgang W Mittelbronn Michel M Angel Peter P Peterziel Heike H

Neuro-oncology 20190201 3

<h4>Background</h4>Treatment options of glioblastoma, the most aggressive primary brain tumor with frequent relapses and high mortality, are still very limited, urgently calling for novel therapeutic targets. Expression of the glycoprotein podoplanin correlates with poor prognosis in various cancer entities, including glioblastoma. Furthermore, podoplanin has been associated with tumor cell migration and proliferation in vitro; however, experimental data on its function in gliomagenesis in vivo ...[more]

PMID: 30418623

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Project description:BackgroundGlioblastoma multiforme (GBM) is the most malignant type of glioma. GBM tumors grow rapidly, have a high degree of malignancy, and are characterized by a fast disease progression. Unfortunately, there is a lack of effective treatments. An effective strategy for the treatment of GBM would be to identify key biomarkers correlating with the occurrence and progression of GBM and developing these biomarkers into therapeutic targets.Method and resultsIn this study, using integrated bioinformatics analysis, we identified differentially expressed genes (DEGs), including 130 genes that were upregulated in GBM compared to normal brain tissue, and 128 genes that were downregulated in GBM. Based on Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis, these genes were associated with regulation of tumor cell adhesion, differentiation, morphology in GBM and were mainly enriched in Complement and coagulation cascades pathway. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to construct a Protein-Protein Interaction network. Ten hub genes were identified, including FN1, CD44, MYC, CDK1, SERPINE1, COL3A1, COL1A2, LOX, POSTN and EZH2, all of which were significantly upregulated in GBM, these results were confirmed by oncomine database exploration. Alteration analysis of hub genes found that patients with alteration in at least one of the hub genes showed shorter median survival times (p = 0.013) and shorter median disease-free survival times (p = 2.488E-3) than patients without alterations in any of the hub genes. Multiple tests for survival analysis showed that among individual hub genes only expression of LOX was correlated with patient survival (P < 0.05).GDS4467 data set was used to analyze the expression of LOX in gliomas with different degrees of malignancy, and it was found that the expression level of LOX was positively correlated with the malignant degree of gliomas.By analyzing GDS 4535 data set showed that the expression level of LOX was positively correlated with the differentiation degree of GBM cells CONCLUSION: This research suggests that FN1, CD44, MYC, CDK1, SERPINE1, COL3A1, COL1A2, LOX, POSTN and EZH2 are key genes in GBM. However, only LOX is correlated with patient survival and promotes glioblastoma cell differentiation and tumor recurrence. LOX may be a candidate prognostic biomarker and potential therapeutic target for GBM.

Project description:BackgroundGlioma is the most common and aggressive tumor in the adult brain. Recent studies have indicated that Zinc finger DHHC-type palmitoyltransferases (ZDHHCs) play vital roles in regulating the progression of glioma. ZDHHC15, a member of the ZDHHCs family, participates in various physiological activities in the brain. However, the biological functions and related mechanisms of ZDHHC15 in glioma remain poorly understood.MethodsData from multiple glioma-associated datasets were used to investigate the expression profiles and potential biological functions of ZDHHC15 in glioma. Expression of ZDHHC15 and its association with clinicopathological characteristics in glioma were validated by quantitative reverse transcription PCR (RT-qPCR) and immunohistochemical experiments. GO enrichment analysis, KEGG analysis, GSEA analysis, CCK-8, EdU, transwell, and western blotting assays were performed to confirm the functions and mechanism of ZDHHC15 in glioma. Moreover, we performed Kaplan-Meier analysis and Cox progression analysis to explore the prognostic significance of ZDHHC15 in glioma patients.ResultsZDHHC15 expression was significantly up-regulated in glioma and positively associated with malignant phenotypes. Results from the GO and KEGG enrichment analysis revealed that ZDHHC15 was involved in regulating cell cycle and migration. Knockdown of ZDHHC15 inhibited glioma cell proliferation and migration, while overexpression of ZDHHC15 presented opposite effects on glioma cells. Besides, results from GSEA analysis suggested that ZDHHC15 was enriched in STAT3 signaling pathway. Knockdown or overexpression of ZDHHC15 indeed affected the activation of STAT3 signaling pathway. Additionally, we identified ZDHHC15 as an independent prognostic biomarker in glioma, and higher expression of ZDHHC15 predicted a poorer prognosis in glioma patients.ConclusionOur findings suggest that ZDHHC15 promotes glioma malignancy and can serve as a novel prognostic biomarker for glioma patients. Targeting ZDHHC15 may be a promising therapeutic strategy for glioma.

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Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma.

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Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma.

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