IDH1 mutation-associated long non-coding RNA expression profile changes in glioma.

Isocitrate dehydrogenase 1 (IDH1) mutation is an important prognostic marker in glioma. However, its downstream effect remains incompletely understood. Long non-coding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis in a number of human malignancies, including glioma. Here, we investigated whether and how lncRNA expression profiles would differ between gliomas with or without IDH1 mutation. By using our previously reported lncRNA mining approach, we performed lncRNA profiling in three public glioma microarray datasets. The differential lncRNA expression analysis was then conducted between mutant-type and wild-type IDH1 glioma samples. Comparison analysis identified 14 and 9 lncRNA probe sets that showed significantly altered expressions in astrocytic and oligodendroglial tumors, respectively (fold change ≥ 1.5, false discovery rate ≤ 0.1). Moreover, the differential expressions of these lncRNAs could be confirmed in the independent testing sets. Functional exploration of the lncRNAs by analyzing the lncRNA-protein interactions revealed that these IDH1 mutation-associated lncRNAs were involved in multiple tumor-associated cellular processes, including metabolism, cell growth and apoptosis. Our data suggest the potential roles of lncRNA in gliomagenesis, and may help to understand the pathogenesis of gliomas associated with IDH1 mutation.

Progesterone Is More Effective Than Dexamethasone in Prolonging Overall Survival and Preserving Neurologic Function in Experimental Animals with Orthotopic Glioblastoma Allografts.

OBJECTIVE: Dexamethasone (DEXA) has been widely used in the management of peritumoral brain edema. DEXA, however, has many systemic side effects and can interact negatively with glioma therapy. Progesterone (PROG), however, is a well-tolerated and readily accessible anti-inflammatory and antiedema agent, with potent neuroprotective properties. We investigated whether PROG could serve as a viable alternative to DEXA in the management of peritumoral brain edema. METHODS: We used an orthotopic C6 glioblastoma model with male Sprague-Dawley rats. Tumor grafts were allowed to grow for 14 days before drug treatment with DEXA 1 mg/kg, PROG 10 mg/kg, or PROG 20 mg/kg for 5 consecutive days. The overall animal survival and neurologic function were evaluated. Mechanistic studies on blood-brain barrier permeability and angiogenic responses were performed on the ex vivo tumor grafts. RESULTS: We found that all drug treatments prolonged overall survival to different extents. PROG 10 mg led to significantly longer survival and better preservation of neurologic function and body weight. The blood-brain barrier permeability was better preserved with PROG 10 mg than with DEXA, possibly through downregulation of matrix metalloproteinase-9 and aquaporin-4 expression. Antiangiogenic responses were also observed in the PROG group. CONCLUSIONS: The present proof-of-concept pilot study has provided novel information on the use of PROG as a corticosteroid-sparing agent in brain tumor management. Further translational and clinical studies are warranted.

MicroRNA-210 and Endoplasmic Reticulum Chaperones in the Regulation of Chemoresistance in Glioblastoma.

Glioblastoma multiforme (GBM) is the commonest primary brain tumour in adults characterized by relentless recurrence due to resistance towards the standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, is known to be upregulated in TMZ-resistant GBM cells. MicroRNAs (miRNAs) are non-protein-coding transcripts that may play important roles in GBM chemoresistance. We surmised that miRNA dysregulations may contribute to P4HB upregulation, hence chemoresistance. We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells. Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance. A reciprocal relationship between their expressions was also verified in clinical glioma specimens. Our study is the first to demonstrate a potential link between miR-210 and ER chaperone in determining chemosensitivity in GBM. The findings have important translational implications in suggesting new directions of future studies.