RESUMO
Intermittent hypoxia in patients with obstructive sleep apnea (OSA) hypopnea syndrome (OSAHS) is associated with pharyngeal cavity collapse during sleep. The effect of human umbilical cord mesenchymal stem cells (HUCMSCs) on OSA-induced oxidative damage in the genioglossus and whether nuclear factor erythroid 2-related factor 2 (Nrf2) or its upstream genes play a key role in this process remains unclear. This study aimed to identify the key factors responsible for oxidative damage during OSAHS through Nrf2 analysis and hypothesize the mechanism of HUCMSC therapy. We simulated OSA using an intermittent hypoxia model, observed the oxidative damage in the genioglossus and changes in Nrf2 expression during intermittent hypoxia, and administered HUCMSCs therapy. Nrf2 initially increased, then decreased, aggravating the oxidative damage in the genioglossus; Nrf2 protein content decreased during hypoxia. Using transcriptomics, we identified seven possible factors in HUCMSCs involved in ameliorating oxidative stress by Nrf2, of which DJ-1 and MEF2A, showing trends similar to Nrf2, were selected by polymerase chain reaction. HUCMSCs may reduce oxidative stress induced by intermittent hypoxia through Nrf2, and the possible upstream target genes in this process are MEF2A and DJ-1. Further studies are needed to verify these findings.
Assuntos
Células-Tronco Mesenquimais , Apneia Obstrutiva do Sono , Humanos , Terapia Baseada em Transplante de Células e Tecidos , Hipóxia/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Cordão Umbilical/metabolismoRESUMO
BACKGROUND: LncRNA SRY-box transcription factor 2 overlapping transcript (SOX2-OT) is linked to multiple cancers, but its specific role and mechanism in head and neck squamous cell carcinoma (HNSCC) remain poorly understood. METHODS: We harnessed clinical data and HNSCC transcriptome profiles from UCSC Xena, TCGA, and GEO databases. Employing various algorithms, we assessed the correlation between SOX2-OT expression and the HNSCC immune microenvironment. Differential expression analysis identified immune-enriched miRNAs (DEmiRNAs) and mRNAs (DEmRNAs). Utilizing miRanda, miRWalk, and Cytoscape, we constructed a ceRNA network encompassing SOX2-OT, DEmiRNAs, and DEmRNAs. A Sankey diagram visualized pivotal SOX2-OT-miRNA-mRNA-pathways. Functional assays validated SOX2-OT silencing effects in HNSCC cells. Luciferase reporter assays verified SOX2-OT/let-7c-3p/SKP2 relationships. Additionally, a xenograft mouse model revealed SOX2-OT's impact on xenograft growth and lung metastasis. RESULTS: SOX2-OT expression demonstrated a predominantly positive correlation with B lineage and VTCN1, while manifesting a negative correlation with Neutrophil and CD47 in HNSCC tissues. We discerned a ceRNA network comprising 65 DEmiRNAs and 116 DEmRNAs, while a protein-protein interaction (PPI) network revealed 97 protein nodes among DEmRNAs. Notably, the Sankey diagram spotlighted six key DEmRNAs intricately linked to the SOX2-OT-regulated DEmiRNAs immune-related pathway. Experimental assays established that SOX2-OT silencing exerted inhibitory effects on cell proliferation, migration, tumor growth, and lung metastasis within HNSCC cells, both in vitro and in vivo. We identified let-7c-3p as a target miRNA of SOX2-OT and SKP2 as a target mRNA of let-7c-3p. CONCLUSIONS: Our study establishes the critical SOX2-OT/let-7c-3p/SKP2 axis as a pivotal regulator of HNSCC tumorigenesis and metastasis.