Mechanism of SOX10 in ferroptosis of hippocampal neurons after intracerebral hemorrhage via the miR-29a-3p/ACSL4 axis.

Intracerebral hemorrhage (ICH) is classified as a lethal neurological injury associated with cerebrovascular disorders. Ferroptosis is a unique form of cell death and participates in ICH pathogenesis. Herein, the role of SRY-box transcription factor 10 (SOX10) in ferroptosis of hippocampal neurons after ICH was investigated. The in vitro ICH models were established by treating immortalized mouse hippocampal cell line HT-22 with Hemin. Quantitative real-time polymerase chain reaction and Western blotting revealed that the transcription factor SOX10 and microRNA (miR)-29a-3p were decreased whereas acyl-CoA synthetase long-chain family member 4 (ACSL4) was increased in the ICH cell models. Subsequently, the assays of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, the commercial kits, and fluorescent labeling revealed that SOX10 overexpression improved cell viability, decreased the amount of reactive oxygen species (ROS) and Fe2+, and increased the amount of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in ICH models. Thereafter, chromatin immunoprecipitation and dual-luciferase assays showed that SOX10 binding to the miR-29a-3p promoter region increased miR-29a-3p expression, and miR-29a-3p targeted and limited ACSL4 transcription. Rescue experiments showed that miR-29a-3p downregulation or ACSL4 overexpression expedited ferroptosis of Hemin-treated HT-22 cells. Taken together, SOX10 contributed to ferroptosis of hippocampal neurons after ICH via increasing miR-29a-3p to limit ACSL4 transcription.NEW & NOTEWORTHY SOX10 promotes the expression of Mir-29a-3p by binding to the promoter region of Mir-29a-3p, thereby targeting the expression of ACSL4 and inhibiting the iron death of hippocampal neuronal cells in mice with ICH.

A Voxel-Based Radiographic Analysis Reveals the Biological Character of Proneural-Mesenchymal Transition in Glioblastoma.

Introduction: Proneural and mesenchymal subtypes are the most distinct demarcated categories in classification scheme, and there is often a shift from proneural type to mesenchymal subtype in the progression of glioblastoma (GBM). The molecular characters are determined by specific genomic methods, however, the application of radiography in clinical practice remains to be further studied. Here, we studied the topography features of GBM in proneural subtype, and further demonstrated the survival characteristics and proneural-mesenchymal transition (PMT) progression of samples by combining with the imaging variables. Methods: Data were acquired from The Cancer Imaging Archive (TCIA, http://cancerimagingarchive.net). The radiography image, clinical variables and transcriptome subtype from 223 samples were used in this study. Proneural and mesenchymal subtype on GBM topography based on overlay and Voxel-based lesion-symptom mapping (VLSM) analysis were revealed. Besides, we carried out the comparison of survival analysis and PMT progression in and outside the VLSM-determined area. Results: The overlay of total GBM and separated image of proneural and mesenchymal subtype revealed a correlation of the two subtypes. By VLSM analysis, proneural subtype was confirmed to be related to left inferior temporal medulla, and no significant voxel was found for mesenchymal subtype. The subsequent comparison between samples in and outside the VLSM-determined area showed difference in overall survival (OS) time, tumor purity, epithelial-mesenchymal transition (EMT) score and clinical variables. Conclusions: PMT progression was determined by radiography approach. GBM samples in the VLSM-determined area tended to harbor the signature of proneural subtype. This study provides a valuable VLSM-determined area related to the predilection site, prognosis and PMT progression by the association between GBM topography and molecular characters.

Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance.

Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (lnc-TALC) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, including lncRNAs, to other cells as a form of intercellular communication. In this study, we found that lnc-TALC could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of lnc-TALC binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited lnc-TALC-mediated TMZ resistance. Our results reveal that exosome-transmitted lnc-TALC could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the lnc-TALC-mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.See related Spotlight by Zhao and Xie, p. 1372.