Research Article: Array expression meta-analysis of cancer stem cell genes identifies upregulation of PODXL especially in DCC low expression meningiomas

Date Published: May 13, 2019

Publisher: Public Library of Science

Author(s): Hans-Juergen Schulten, Deema Hussein, Aamir Ahmad.


Meningiomas are the most common intracranial tumors, with a subset of cases bearing a progressive phenotype. The DCC netrin 1 receptor (DCC) is a candidate gene for early meningioma progression. Cancer stem cell (CSC) genes are emerging as cancer therapeutic targets, as their expression is frequently associated with aggressive tumor phenotypes. The main objective of the study was to identify deregulated CSC genes in meningiomas.

Interrogating two expression data repositories, significantly differentially expressed genes (DEGs) were determined using DCC low vs. DCC high expression groups and WHO grade I (GI) vs. grade II + grade III (GII + GIII) comparison groups. Human stem cell (SC) genes were compiled from two published data sets and were extracted from the DEG lists. Biofunctional analysis was performed to assess associations between genes or molecules.

In the DCC low vs. DCC high expression groups, we assessed seven studies representing each between seven and 58 samples. The type I transmembrane protein podocalyxin like (PODXL) was markedly upregulated in DCC low expression meningiomas in six studies. Other CSC genes repeatedly deregulated included, e.g., BMP/retinoic acid inducible neural specific 1 (BRINP1), prominin 1 (PROM1), solute carrier family 24 member 3 (SLC24A3), rRho GTPase activating protein 28 (ARHGAP28), Kruppel like factor 5 (KLF5), and leucine rich repeat containing G protein-coupled receptor 4 (LGR4). In the GI vs. GII + GIII comparison groups, we assessed six studies representing each between nine and 68 samples. DNA topoisomerase 2-alpha (TOP2A) was markedly upregulated in GII + GIII meningiomas in four studies. Other CSC genes repeatedly deregulated included, e.g., ARHGAP28 and PODXL. Network analysis revealed associations of molecules with, e.g., cellular development and movement; nervous system development and function; and cancer.

This meta-analysis on meningiomas identified a comprehensive list of deregulated CSC genes across different array expression studies. Especially, PODXL is of interest for functional assessment in progressive meningiomas.

Partial Text

Based on ultrastructural and histologic similarities, meningiomas are described to originate from arachnoidal cells. Meningiomas account for approximately 30% of all primary intracranial brain tumors [1]. The majority of meningiomas are considered benign and are commonly treated by surgery; however, a minority of cases progress further or recur. The clinical behavior of meningiomas is assessed by using the grading system where benign meningiomas are classified as WHO grade I (GI) tumors and more aggressive meningiomas as atypical, grade II (GII) tumors, or as anaplastic, grade III (GIII) tumors. Molecular markers predicting aggressiveness of meningiomas are not well-known [2].

Using the search query in GEO and ArrayExpress, identified 37 and 27 data sets, respectively (Fig 1). Exclusion criteria from the repositories included data sets that used custom-made, SNP or miRNA arrays; used discontinued array types or brands; contained < 6 meningioma samples or only in vitro/in vivo samples; comprised not the binary CEL files; or were reanalyzed data sets. Two data sets using HuGene 1.0 ST arrays were performed in the same laboratory and samples were pooled for subsequent analysis. In sum, eight studies from both repositories were selected for further analysis (Table 1). Two of eight studies used HuGene 1.0 ST arrays, one study used HuGene 2.1 ST arrays strips, and five studies employed U133 Plus 2.0 arrays. HuGene 1.0 ST arrays and HuGene 2.1 ST arrays strips represent whole transcript chips that interrogate gene expression levels on average with one probe per exon. In contrast, the U133 Plus 2.0 arrays interrogate expression levels primarily at the 3`-region of the genes. Seven selected studies met the criteria to establish sets of differentially expressed CSC genes from the DCC low vs. DCC high expression groups (Fig 2 and S1 Fig) whereas six studies met the criteria to establish sets of differentially expressed CSC genes from the GI vs. GII + GIII comparison groups [16, 28–35]. In our biostatistical meta-analysis, we identified CSC genes that, according to their expression profiles, are seemingly associated with DCC low expression meningiomas and, in their content, have not been reported before. We combined two resources to compile a list of SC genes that were used to identify differentially expressed CSC genes, which may exert a function in development and/or progression of meningiomas. One resource generated a reference list containing 250 human SC genes that were detected by transcriptome sequencing (RNA-seq) in cultured human amniocytes, or ESC and iPSC and were reported to have a functional relevance in SC maintenance. The authors commented that amniocytes inhere a unique SC identity and exist in a developmentally intermediate, hence uncommitted state [23]. The other resource employed cell surface capture technology and expression array assays to compile a list of 120 human PSC surface N-glycoproteins that were separated from those proteins that were also abundantly expressed in human fibroblasts or other non-diseased tissues [24]. The authors stated that the development of the cell surface capture technology enabled identification of proteins that otherwise are rarely detectable at the transcriptional level.   Source: