PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation.
Marta ChiavariGabriella Maria Pia CiottiFrancesco CanonicoFabio AltieriPedro Miguel LacalGrazia GrazianiPierluigi NavarraLucia LisiPublished in: International journal of molecular sciences (2020)
The glioblastoma (GB) microenvironment includes cells of the innate immune system identified as glioma-associated microglia/macrophages (GAMs) that are still poorly characterized. A potential role on the mechanisms regulating GAM activity might be played by the endoplasmic reticulum protein ERp57/PDIA3 (protein disulfide-isomerase A3), the modulation of which has been reported in a variety of cancers. Moreover, by using The Cancer Genome Atlas database, we found that overexpression of PDIA3 correlated with about 55% reduction of overall survival of glioma patients. Therefore, we analyzed the expression of ERp57/PDIA3 using specimens obtained after surgery from 18 GB patients. Immunohistochemical analysis of tumor samples revealed ERp57/PDIA3 expression in GB cells as well as in GAMs. The ERp57/PDIA3 levels were higher in GAMs than in the microglia present in the surrounding parenchyma. Therefore, we studied the role of PDIA3 modulation in microglia-glioma interaction, based on the ability of conditioned media collected from human GB cells to induce the activation of microglial cells. The results indicated that reduced PDIA3 expression/activity in GB cells significantly limited the microglia pro-tumor polarization towards the M2 phenotype and the production of pro-inflammatory factors. Our data support a role of PDIA3 expression in GB-mediated protumor activation of microglia.
Keyphrases
- induced apoptosis
- poor prognosis
- inflammatory response
- cell cycle arrest
- end stage renal disease
- neuropathic pain
- binding protein
- stem cells
- endoplasmic reticulum
- newly diagnosed
- ejection fraction
- chronic kidney disease
- squamous cell carcinoma
- immune response
- long non coding rna
- prognostic factors
- peritoneal dialysis
- machine learning
- signaling pathway
- small molecule
- deep learning
- patient reported
- big data
- amino acid
- data analysis
- protein protein