Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

Armento, Angela; Ilina, Elena I.; Kaoma, Tony; Muller, Arnaud; Vallar, Laurent; Niclou, Simone P.; Krüger, Marcel A.; Mittelbronn, Michel; Naumann, Ulrike

doi:10.3892/ijo.2017.4051

Cited by 14 publications

(15 citation statements)

References 43 publications

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“…CPE is a peptidase which may also function as a neurotrophic factor promoting neuronal survival. Interestingly, CPE has been found to be secreted by cultured astrocytes (Klein et al, 1992) and its overexpression in a mouse model of glioma was found to mitigate cell migration (Armento et al, 2017). Through transwell assays, astrocyte cortex subpopulation C was identified as having less migratory potential than subpopulation A (John Lin et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Brain Region-Specific Gene Signatures Revealed by Distinct Astrocyte Subpopulations Unveil Links to Glioma and Neurodegenerative Diseases

Duran

Wang

Zheng³

et al. 2019

eNeuro

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Currently, there are no effective treatments for glioma or for neurodegenerative diseases because of, in part, our limited understanding of the pathophysiology and cellular heterogeneity of these diseases. Mounting evidence suggests that astrocytes play an active role in the pathogenesis of these diseases by contributing to a diverse range of pathophysiological states. In a previous study, five molecularly distinct astrocyte subpopulations from three different brain regions were identified. To further delineate the underlying diversity of these populations, we obtained mouse brain region-specific gene signatures for both protein-coding and long non-coding RNA and found that these astrocyte subpopulations are endowed with unique molecular signatures across diverse brain regions. Additional gene set and single-sample enrichment analyses revealed that gene signatures of different subpopulations are differentially correlated with glioma tumors that harbor distinct genomic alterations. To the best of our knowledge, this is the first study that links transcriptional profiles of astrocyte subpopulations with glioma genomic mutations. Furthermore, our results demonstrated that subpopulations of astrocytes in select brain regions are associated with specific neurodegenerative diseases. Overall, the present study provides a new perspective for understanding the pathophysiology of glioma and neurodegenerative diseases and highlights the potential contributions of diverse astrocyte populations to normal, malignant, and degenerative brain functions.

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Section: Discussionmentioning

confidence: 99%

Brain Region-Specific Gene Signatures Revealed by Distinct Astrocyte Subpopulations Unveil Links to Glioma and Neurodegenerative Diseases

Duran

Wang

Zheng³

et al. 2019

eNeuro

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“…CPE knock-out mice are obese, diabetic, infertile, and exhibit poor memory and learning. CPE has been shown to be involved in tumorigenesis and cancer progression [5,6,7]. Clinical studies have demonstrated that elevated CPE mRNA and protein levels are correlated with poor prognosis in colorectal [8], hepatocellular carcinoma [9], and cervical cancer patients [10].…”

Section: Introductionmentioning

confidence: 99%

Carboxypeptidase E-∆N Promotes Proliferation and Invasion of Pancreatic Cancer Cells via Upregulation of CXCR2 Gene Expression

Hareendran

Yang

et al. 2019

IJMS

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Pancreatic cancer is one of the leading causes of cancer-related mortality worldwide. The molecular basis for the pathogenesis of this disease remains elusive. In this study, we have investigated the role of wild-type Carboxypeptidase E (CPE-WT) and a 40 kDa N-terminal truncated isoform, CPE-ΔN in promoting proliferation and invasion of Panc-1 cells, a pancreatic cancer cell line. Both CPE-WT and CPE-ΔN were expressed in Panc-1 and BXPC-3 pancreatic cancer cells. Immunocytochemical studies revealed that in CPE transfected Panc-1 cells, CPE-ΔN was found primarily in the nucleus, whereas CPE-WT was present exclusively in the cytoplasm as puncta, characteristic of secretory vesicles. Endogenous CPE-WT was secreted into the media. Overexpression of CPE-ΔN in Panc-1 cells resulted in enhancement of proliferation and invasion of these cells, as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell proliferation assay and Matrigel invasion assay, respectively. In contrast, the expression of CPE-WT protein at comparable levels to CPE-ΔN in Panc-1 cells resulted in promotion of proliferation but not invasion. Importantly, there was an upregulation of the expression of CXCR2 mRNA and protein in Panc-1 cells overexpressing CPE-ΔN, and these cells exhibited significant increase in proliferation in a CXCR2-dependent manner. Thus, CPE-ΔN may play an important role in promoting pancreatic cancer growth and malignancy through upregulating the expression of the metastasis-related gene, CXCR2.

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“…Overexpression of CPE diminished glioma cell migration [53]. An increase in secreted CPE (sCPE) affected mRNAs levels of genes connected to the motility-associated networks, such as FAK, PAK, Cdc42, integrin, STAT3, and TGF-β [54]. Moreover, sCPE enhanced glucose flux into the tricarboxylic acid cycle at the expense of lactate production; this change reduced aerobic glycolysis, possibly contributing to a less invasive behavior of tumor cells [55].…”

Section: Serbp1 As a New Regulator Of Cancer Metabolismmentioning

confidence: 99%

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation

Kosti

Araújo

et al. 2020

Genome Biol

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Background: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy. Results: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo-and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites. Conclusions: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.

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Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors

Cited by 14 publications

References 43 publications

Brain Region-Specific Gene Signatures Revealed by Distinct Astrocyte Subpopulations Unveil Links to Glioma and Neurodegenerative Diseases

Brain Region-Specific Gene Signatures Revealed by Distinct Astrocyte Subpopulations Unveil Links to Glioma and Neurodegenerative Diseases

Carboxypeptidase E-∆N Promotes Proliferation and Invasion of Pancreatic Cancer Cells via Upregulation of CXCR2 Gene Expression

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation

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