RESUMEN
Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)-a negative KDM5C target-and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Línea Celular Tumoral , Cromatina/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Humanos , Hipoxia/genética , Interleucina-6/metabolismo , Lisina/metabolismo , Oxígeno/metabolismo , Survivin/genética , Factores de Transcripción/metabolismo , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Transient dysphagia after anterior cervical discectomy is not uncommon. It is usually related to esophageal edema secondary to retraction, mechanical adhesions of the esophagus to the anterior spine, and stretch injuries to nerves involved in the swallowing mechanism. Structurally induced dysphagia, secondary to laceration of the neck viscera or to the presence of retropharyngeal masses, is by far less frequent, and it does not usually improve over time. CASE DESCRIPTION: The authors present the case of a 36-year-old woman who complained of severe dysphagia both for solids and liquids after C4 through C5 anterior discectomy and fusion, complicated by a millimetric dural tear of the anterior thecal sac. Postoperative neuroimaging revealed retropharyngeal fluid collection, extending in front of the vertebral bodies of C3, C4, and C5, exerting a mass effect on the posterior wall of the pharynx. Taking into account both the MRI aspect of the collection and the dramatic improvement of symptoms after lumbar punctures, we conducted a diagnosis of CSF collection in continuity with the subarachnoid space. The dysphagia and the CSF collection resolved with conservative therapy (bed rest and 3 lumbar punctures). CONCLUSION: To the best of our knowledge, such a complication has never been described before in the literature. It should be included in the differential diagnosis of patients with postoperative dysphagia lasting more than 48 hours.