Dataset Information

Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition.

ABSTRACT: Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. To establish, the crucial role of the hypoxic pathways in pHGGs, we, first, assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs and in pHGG's cell lines, cultured in both normoxic and hypoxic conditions. Secondly, based on the concept of a bi-therapy targeting in pHGGs mTORC1 (rapamycin) and HIF-1α (irinotecan), we hypothesized that the balanced expressions between RAS/ERK, PI3K/AKT and HIF-1α/HIF-2α/MYC proteins or genes may provide a modulation of the cell response to this double targeting. Finally, we could evidence three protein, genomic and metabolomic profiles of response to rapamycin combined with irinotecan. The pattern of highly sensitive cells to mTOR/HIF-1α targeting was linked to a MYC/ERK/HIF-1α over-expression and the cell resistance to a major hyper-expression of HIF-2α.

SUBMITTER: Nguyen A

PROVIDER: S-EPMC5641075 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition.

Nguyen Aurélia A Moussallieh François Marie FM Mackay Alan A Cicek A Ercument AE Coca Andres A Chenard Marie Pierre MP Weingertner Noelle N Lhermitte Benoit B Letouzé Eric E Guérin Eric E Pencreach Erwan E Jannier Sarah S Guenot Dominique D Namer Izzie Jacques IJ Jones Chris C Entz-Werlé Natacha N

Oncotarget 20170323 42

Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironmen ...[more]

PMID: 29069732

Similar Datasets

Project description:Purpose of reviewPediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy. Chemotherapy remains the preferred first-line therapy for adjuvant treatment of the majority of recurrent or progressive pLGG.Recent findingsTechnologic advances offer the potential to limit volume of normal brain exposed to low doses of radiation when treating pLGG with either conformal photon or proton RT. Recent neurosurgical techniques such as laser interstitial thermal therapy offer a "dual" diagnostic and therapeutic treatment modality for pLGG in specific surgically inaccessible anatomical locations. The emergence of novel molecular diagnostic tools has enabled scientific discoveries elucidating driver alterations in mitogen-activated protein kinase (MAPK) pathway components and enhanced our understanding of the natural history (oncogenic senescence). Molecular characterization strongly supplements the clinical risk stratification (age, extent of resection, histological grade) to improve diagnostic precision and accuracy, prognostication, and can lead to the identification of patients who stand to benefit from precision medicine treatment approaches. The success of molecular targeted therapy (BRAF inhibitors and/or MEK inhibitors) in the recurrent setting has led to a gradual and yet significant paradigm shift in the treatment of pLGG. Ongoing randomized trials comparing targeted therapy to standard of care chemotherapy are anticipated to further inform the approach to upfront management of pLGG patients.

Project description:CircRNAs play an important role in various physiological and pathological biological processes. Despite their widespread involvement, the function of circRNAs in intermittent hypoxia (IH) remain incompletely understood. This study aims to clarify the molecular mechanism of it in IH. Differentially expressed circRNAs were identified by transcriptome sequencing analysis in intermittent hypoxia (IH) model. GO and KEGG enrichment analys were performed on the identified differentially expressed circRNAs. The circular characteristics of hsa_circ_0081065 in human umbilical vein endothelial cells (HUVECs) were detected by RT-qPCR. The sublocalization of hsa_circ_0081065 was examined by FISH. The effect of hsa_circ_0081065 on endothelial to mesenchymal transition (EndMT) was estimated by detecting the expression of EndMT related markers. Various techniques, including RNA-pull down, RIP, EMSA, dual-luciferase reporter assay and immunofluorescence staining were used to investigate the relationship among hsa_circ_0081065, miR-665 and HIF-1α. A total of 13,304 circRNAs were identified in HUVECs treatment with IH, among which 73 were differentially expressed, including 24 upregulated circRNAs and 49 downregulated circRNAs. Notably, hsa_circ_0081065 demonstrated a significantly upregulation. Hsa_circ_0081065 exhibited the circular characteristics of circRNA and was predominantly localized in the cytoplasm. Knockdown of hsa_circ_0081065 inhibited EndMT. Mechanically, we demonstrated that hsa_circ_0081065 acts as a sponge for miR-665 to up-regulate HIF-1α and exacerbate HIF-1α nuclear translocation in HUVECs. We have demonstrated that hsa_circ_0081065 is significantly upregulated in HUVECs treated with IH. Our findings indicate that hsa_circ_0081065 exacerbates IH-induced EndMT through the regulation of the miR-665/HIF-1α signal axis and facilitating HIF-1α nuclear translocation. These results provide a theoretical basis for considering of EndMT as a potential therapeutic target for OSAHS intervention.

Dataset Information

Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition.

Publications

Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets