Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor responsible for the expression of a broad range of genes that facilitate acclimatization to hypoxia. Its stability is predominantly controlled by rapid hydroxylation of two proline residues in its α-subunit. However, how the rapid hydroxylation of HIF-1α is regulated is not fully understood. Here, we report that transient receptor potential canonical (TRPC) 6 channels control hydroxylation and stability of HIF-1α in human glioma cells under hypoxia. TRPC6 was rapidly activated by IGF-1R–PLCγ–IP₃R pathway upon hypoxia. Inhibition of TRPC6 enhanced the levels of α-ketoglutarate and promoted hydroxylation of HIF-1α to suppress HIF-1α accumulation without affecting its transcription or translation. Dimethyloxalylglycine N-(methoxyoxoacetyl)-glycine methyl ester (DMOG), an analog of α-ketoglutarate, reversed the inhibition of HIF-1α accumulation. Moreover, TRPC6 regulated GLUT1 (also known as SLC2A1) expression in a manner that was dependent on HIF-1α accumulation to affect glucose uptake during hypoxia. Our results suggest that TRPC6 regulates metabolism to affect HIF-1α stability and consequent glucose metabolism in human glioma cells under hypoxia.

Accumulating evidence reveals that ferroptosis and pyroptosis play pivotal roles in tumorigenesis of low-grade glioma (LGG). In this research, we aimed to classify molecular subtypes and further identify and verify a novel multigene signature in LGG on the basis of ferroptosis and pyroptosis-related genes (FPRGs). Raw sequencing data and corresponding clinical data of LGG samples retrieved from the TCGA and CGGA databases were obtained for the training and validation datasets. Non-negative matrix factorization (NMF) clustering defined by FPRGs associated with prognosis was performed to classify molecular subtypes of LGG patients. LASSO-SVM-Random Forest analysis was carried out to develop an FPRG signature to predict the survival and benefit of immunotherapy of LGG patients. NMF clustering defined by FPRGs with prognostic values acted to categorize LGG patients into two molecular subtypes with different prognosis, clinical traits and immune microenvironments. A six-FPRG prognostic signature was constructed, accompanied by the optimal p-value. The AUC values of our signature exhibited great prognostic performances. Our signature was superior to other four well-recognized signatures in predicting the survival probability of LGG patients. Immune characteristics, tumor mutation profile, tumor stemness indices, MGMT methylation and immunotherapy response biomarkers showed significant differences between high- and low-risk populations. Finally, a nomogram was created for quantitative prediction of the survival probability of LGG patients, with the AUC values of the nomogram being 0.916, 0.888 and 0.836 for 1-, 3- and 5-year survival, sequentially. Overall, the FPRG signature may function as an effective indicator for the prognosis prediction and immunotherapy response of LGG patients.

Nuclear protein-1 (NUPR1), also named as p8 or Com1, has been since found overexpressed in several human malignant tumor cells, such as glioma. NUPR1 also regulates cell cycle progression, however, the role of NUPR1 in regulating glioma cell cycle remains poorly understood. Knockdown efficiency of U87 and U251 cells infected with the lentiviral vector was detected by quantitative real-time PCR and western blot in vitro and in vivo. Flow cytometry and western blot were used to explore a mechanism by which NUPR1 modulates cell cycle in U87 and U251 cells. Immunohistochemistry was applied to detect expression levels of P27, CDK2, and cyclin E in human glioma tissues with NUPR1 positive expression and tumorigenesis in nude mice. We confirmed that the downregulation of NUPR1 arrested the cell cycle in the G0/G1 phase in U87 and U251 cells in vitro. Furthermore, the expression level of P27 was increased, and CDK2 and cyclin E were decreased upon silencing NUPR1 expression in vitro and in vivo. In conclusion, the knockdown of NUPR1 induces cell cycle arrest in the G0/G1 phase in glioma cells via P27.

Temporal muscle thickness measured on 3D MRI has recently been linked to prognosis in glioblastoma patients and may serve as an independent prognostic indicator. This single-center study looked at temporal muscle thickness and prognosis in patients with primary glioblastoma. Overall survival was the major study outcome. For a retrospective analysis from 2010 to 2020, clinical data from 102 patients with glioblastoma at the Department of Oncology Radiotherapy of the First Affiliated Hospital of Dalian Medical University were gathered. Fifty-five cases from 2016 to 2020 contained glioblastoma molecular typing data, of which 45 were IDH wild-type glioblastomas and were analysed separately. TMT was measured on enhanced T1-weighted magnetic resonance images in patients with newly diagnosed glioblastoma.Overall patient survival (OS) was calculated by the Kaplan–Meier method and survival curves were plotted using the log-rank-sum test to determine differences between groups, and multifactorial analyses were performed using a Cox proportional-risk model.The median TMT for 102 patients was 6.775 mm (range: 4.95–10.45 mm). Patients were grouped according to median TMT, and the median overall survival (23.0 months) was significantly longer in the TMT > median group than in the TMT median group (P 0.001; Log-rank test). Analysing 45 patients with IDH wild type alone, the median overall survival (12 months) of patients in the TMT > median group was significantly longer than that of patients in the TMT ≤ median group (8 months) (P < 0.001; Log-rank test).TMT can serve as an independent prognostic factor for glioblastoma.