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Nasopharyngeal carcinoma (NPC) is a common malignant cancer in southern China that has highly invasive and metastatic features and causes high mortality, but the underlying mechanisms of this malignancy remain unclear. In this study, we utilized ChIP-Seq to identify metastasis-specific super enhancers (SEs) and found that the SE of LOC100506178 existed only in metastatic NPC cells and powerfully aggravated NPC metastasis. This metastatic SE transcribed into lncRNA LOC100506178, and it was verified as a seRNA through GRO-Seq. Furthermore, SE-derived seRNA LOC100506178 was found to be highly expressed in metastatic NPC cells and NPC lymph node metastatic tissues. Knockdown of seRNA LOC100506178 arrested the invasion and metastasis of NPC cells in vitro and in vivo, demonstrating that seRNA LOC100506178 accelerates the acquisition of NPC malignant phenotype. Mechanistic studies revealed that seRNA LOC100506178 specifically interacted with the transcription factor hnRNPK and modulated the expression of hnRNPK. Further, hnRNPK in combination with the promoter region of MICAL2 increased Mical2 transcription. Knockdown of seRNA LOC100506178 or hnRNPK markedly repressed MICAL2, Vimentin and Snail expression and upregulated E-cadherin expression. Overexpression of seRNA LOC100506178 or hnRNPK markedly increased MICAL2, Vimentin and Snail expression and decreased E-cadherin expression. Therefore, seRNA LOC100506178 may promote MICAL2 expression by upregulating hnRNPK, subsequently enhancing EMT process and accelerating the invasion and metastasis of NPC cells. seRNA LOC100506178 has the potential to serve as a novel prognostic biomarker and therapeutic target in NPC patients.

Fibroblast-like synoviocytes (FLSs) contribute to the advancement of rheumatoid arthritis (RA) through enhanced metabolic reprogramming. This research focused on exploring the role and underlying mechanism of ubiquitin-specific protease 5 (USP5) in modulating the glycolysis and activation of RA-FLSs. Here, we identified that knockdown of USP5 in RA rats reduced synovial inflammation and glycolytic activity, as evidenced by decreased serum lactate levels and GLUT1 expression. In RA-FLSs, USP5 knockdown or treatment with 2-DG reduced cell proliferation, migration, invasion, cytokine production, and glycolysis, while increased apoptosis. Mechanistically, USP5 stabilized METTL14 by inhibiting its ubiquitination, while METTL14 enhanced the m 6 A modification of GLUT1 mRNA, thereby increasing its expression. Furthermore, overexpression of METTL14 partially reversed the effects of USP5 knockdown on glycolysis and inflammatory activation in RA-FLSs. Additionally, knockdown of METTL14 inhibited RA-FLS glycolysis and inflammatory activation by downregulating GLUT1. Collectively, USP5 stabilized METTL14-mediated m 6 A modification of GLUT1 by inhibiting the ubiquitination of METTL14, thereby enhancing glycolysis and inflammatory activation in RA-FLSs. These results suggest that the USP5/METTL14/GLUT1 axis could be a potential therapeutic target for RA. Highlights USP5 enhances glycolysis and activation of rheumatoid arthritis fibroblast-like synoviocytes via METTL14. METTL14 deubiquitination and stabilization by USP5 enhance the m 6 A modification of GLUT1 mRNA in rheumatoid arthritis. METTL14 promotes GLUT1-dependent glycolysis and activation of rheumatoid arthritis fibroblast-like synoviocytes. Targeting the USP5/METTL14/GLUT1 axis offers a potential therapeutic strategy for rheumatoid arthritis.

The prognosis of gliomas is poor and there are limited therapeutic approaches. Immunotherapy has become a promising treatment for gliomas. Here, we explored the expression pattern of Lck/yes-related protein tyrosine kinase (LYN) in gliomas and assessed its value as an immunotherapy biomarker. Transcriptional data was mined from two publicly available datasets, TCGA and CGGA, and used to investigate the correlation between LYN and clinical characteristics including patient prognosis, somatic mutation, and immune infiltrating features in gliomas. Besides, the correlation between LYN and classical immune checkpoint molecules was explored. Glioma samples obtained from the Xiangya Hospital cohort were used for immunohistochemistry staining. High expression level of LYN was observed in advanced gliomas and other cancer types, which predicted a worse prognosis. LYN stratified patients’ survival in the Xiangya cohort and was also significantly associated with infiltrating immune cell types and inflammatory activities in the tumor microenvironment. LYN was involved in tumor mutation, correlated with the regulation of oncogenic genes, and also showed a significant positive correlation with PD-L1. LYN can be a potential diagnostic marker and immunotherapy marker in gliomas.

Breast cancer (BC) is the most common malignant disease worldwide. Although the survival rate is improved in recent years, the prognosis is still bleak once recurrence and metastasis occur. It is vital to investigate more efficient biomarkers for predicting the metastasis and relapse of BC. DYNLT1 has been reported that participating in the progression of multiple cancers. However, there is still a lack of study about the correlation between DYNLT1 and BC. In this study, we evaluated and validated the expression pattern and prognostic implication of DYNLT1 in BC with multiple public cohorts and BC tumor microarrays (TMAs) of paraffin-embedded tissues collected from the Affiliated Hospital of Jining Medical University. The response biomarkers for immune therapy, such as tumor mutational burden (TMB), between different DYNLT1 expression level BC samples were investigated using data from the TCGA-BRCA cohort utilizing public online tools. In addition, colony formation and transwell assay were conducted to verify the effects of DYNLT1 in BC cell line proliferation and invasion. The results demonstrated that DYNLT1 overexpressed in BC and predicted poor relapse-free survival in our own BC TMA cohort. In addition, DYNLT1 induced BC development by promoting MDA-MB-231 cell proliferation migration, and metastasis. Altogether, our findings proposed that DYNLT1 could be a diagnostic and prognostic indicator in BC.

[This corrects the article DOI: 10.3389/fmed.2023.1167676.].

Cerebral ischemic stroke is a cerebrovascular disease, which is related to DNA damage. Many researches have shown that Ku70 is a key regulator for DNA damage. Here, we aimed to explore Ku70 roles in cerebral ischemic stroke and its potential molecular mechanism. In our study, neural stem cells (NSCs) were induced by oxygen-glucose deprivation/reoxygenation (OGD/R) for constructing cerebral ischemic stroke cell model. CCK8 assay, Brdu/GFP staining, flow cytometry and TUNEL staining were performed to examine cell proliferation, cell cycle and apoptosis, respectively. Relative mRNA and protein levels were detected by quantitative real-time PCR and western blot analysis, respectively. Ku70 positive cells were examined by immunofluorescence staining. Comet assay was employed to determine DNA damage. Animal experiments were performed to assess the effect of transplanting NSCs and Ku70-overexpressed NSCs on neurological deficits, infarct volume, brain edema and blood‒brain barrier (BBB) integrity in middle cerebral artery occlusion (MCAO) model. Our data found that Ku70 expression was decreased in NSCs after OGD/R. Overexpression of Ku70 reduced DNA damage and apoptosis of OGD/R-induced NSCs. Knockdown of Ku70 promoted the activity of ATM/p53. Moreover, KU60019 (ATM-specific inhibitor) reversed the promoting effects of Ku70 silencing on DNA damage and apoptosis in OGD/R-induced NSCs. In animal experiments, transplantation of NSCs-overexpressed Ku70 enhanced cell survival, improved motor function, reduced infarct volume, relieved brain edema and alleviated BBB dysfunction in MCAO mice models. In conclusion, Ku70 overexpression repressed the DNA damage and apoptosis in OGD/R-induced NSCs by regulating ATM/p53 pathway, and transplantation of NSCs-overexpressed Ku70 played neuroprotective effects in MCAO mice models.

The abnormal expression of circular RNA (circRNA) has been implicated in the development of many human diseases, including acute ischemic stroke (AIS). However, the role and mechanism of circ_0029941 in AIS progression remain unclear. Transient middle cerebral artery occlusion (tMCAO) was constructed to mimic AIS mice model, and oxygen–glucose deprivation/reoxygenation (OGD/R)-induced astrocytes were used to mimic AIS cell model. The expression of circ_0029941, eukaryotic translation initiation factor 4A-III (EIF4A3), microRNA (miR)-224-5p and nuclear factor activated T cell 5 (NFAT5) were determined by quantitative real-time PCR. Triphenyl tetrazolium chloride staining was used to evaluate infarct size in mice, and immunostaining was performed to confirm GFAP, MAP1LC3B, and NFAT5 levels. Protein expression was tested by western blot analysis, and FISH was used for co-location. The interaction between circ_0029941 and miR-224-5p was verified by RIP and RNA pull-down assays. And the interaction between miR-224-5p and NFAT5 was confirmed by RIP and dual-luciferase reporter assays. Circ_0029941 had elevated expression in AIS patients, tMCAO models and OGD/R-induced astrocytes. Knockdown of circ_0029941 alleviated brain infarction in tMCAO mice. Also, circ_0029941 knockdown inhibited astrocyte activation and ATG5-mediated autophagy. In addition, EIF4A3 promoted circ_0029941 level, and circ_0029941 sponged miR-224-5p to regulate NFAT5. Besides, miR-224-5p inhibitor or NFAT5 overexpression reversed the inhibition effect of circ_0029941 knockdown on astrocyte activation and autophagy. In addition, antagomiR-224-5p also abolished the relieving effect of circ_0029941 knockdown on brain infarction of tMCAO mice. EIF4A3-induced circ_0029941 promoted astrocyte activation and autophagy through regulating the miR-224-5p/NFAT5 axis.

Background : Lactylation, a novel lactate-derived posttranslational modification, has been demonstrated to be linked with brain function. The present research is intended to explore the role of β-arrestin1 (ARRB1) lactylation post-subarachnoid hemorrhage (SAH). Methods : SAH models were established in mice via intravascular puncture and in primary neurons by oxyhemoglobin (oxyHb) stimulation. Lactylome analysis identified differentially lactylated proteins. Commercial kits measured lactate, mitochondrial membrane potential, reactive oxygen species (ROS), and ATP. Mitochondrial respiration was evaluated by detecting mitochondrial oxygen consumption rate. Cell viability and apoptosis were respectively determined by CCK-8 assay and flow cytometry/TUNEL assay. Protein interactions were assessed using co-immunoprecipitation and double-label immunofluorescence. Results : Elevated lactate and ARRB1 lactylation were observed in the brain of SAH mice. In primary neurons, reducing lactate with oxamate reversed mitochondrial dysfunction and apoptosis induced by oxyHb. Overexpression of ARRB1 exacerbated oxyHb-induced neuronal injury, yet this effect was absent with the ARRB1-lysine (K) 195 arginine (R) mutant. E1A binding protein P300 (P300) promoted ARRB1 lactylation to upregulate its protein expression. P300 knockdown inhibited oxyHb-induced neuronal injury, but this inhibitory effect was counteracted by ARRB1 overexpression. In oxyHb-stimulated neurons, ARRB1 lactylation upregulated S100 calcium binding protein A9 (S100A9) protein. Additionally, ARRB1 knockdown prevented mitochondrial respiratory dysfunction in neurons induced by oxyHb, which was antagonized by recombinant S100A9. ARRB1 silencing mitigated SAH injury in mice via suppressing S100A9-mediated mitochondrial dysfunction. Conclusion : P300 mediated ARRB1 lactylation, thereby increasing S100A9 to facilitate mitochondrial dysfunction and neuronal apoptosis in SAH. This study may provide prospective targets for improving SAH.

Background Our previous study demonstrated that olfactory mucosa mesenchymal stem cell (OM‐MSC) neuronal differentiation can reduce neural damage following intracerebral hemorrhage (ICH). However, the mechanisms that regulate OM‐MSC neuronal differentiation to mitigate ICH‐induced brain injury remain unclear. Methods The ICH model was established through autologous blood injection to evaluate the impact of OM‐MSCs on brain injury, using the mNSS method, TUNEL, and Nissl staining, as well as the Western blot assay. qPCR, Western blotting, flow cytometry, and immunofluorescence assays were employed to assess the neuronal differentiation of OM‐MSCs. The SUMOylation assay was conducted to investigate the relationship between IGF2BP2 and SENP1. RIP, RNA pull‐down, and mRNA stability assays were performed to analyze the molecular interaction network involving SENP1, IGF2BP2, and SOX11. Results IGF2BP2 enhanced the protective effects of OM‐MSCs against ICH‐induced brain injury, as demonstrated by a significant reduction in brain edema, mNSS scores, and apoptosis, along with improved neuronal survival. Furthermore, the overexpression of IGF2BP2 increased the expression of Tuj‐1, MAP2, NF200, and NeuN, while decreasing GFAP and ALDH1L1 levels, suggesting the stimulatory effects of IGF2BP2 on the neuronal differentiation of OM‐MSCs. Mechanistically, SENP1 enhanced IGF2BP2 expression through SUMO1‐induced IGF2BP2 SUMOylation. Additionally, IGF2BP2 functioned as an RNA‐binding protein for SOX11, thereby increasing SOX11 levels. The depletion of IGF2BP2 negated the SENP1‐induced neuronal differentiation of OM‐MSCs. The overexpression of SOX11 mitigated the inhibitory effects of IGF2BP2 silencing on OM‐MSC neuronal differentiation. Conclusion The SENP1/IGF2BP2/SOX11 axis played a crucial role in the neuronal differentiation of OM‐MSCs and ameliorated brain damage caused by ICH. IGF2BP2 expression is enhanced by SENP1 through the regulation of SUMO1‐induced IGF2BP2 SUMOylation. Additionally, IGF2BP2 promotes the neuronal differentiation of olfactory mucosa‐mesenchymal stem cells (OM‐MSCs) by stabilizing SOX11, which helps to mitigate brain injury following intracerebral hemorrhage.

Fibroblast-like synoviocytes (FLSs) contribute to the advancement of rheumatoid arthritis (RA) through enhanced metabolic reprogramming. This research focused on exploring the role and underlying mechanism of ubiquitin-specific protease 5 (USP5) in modulating the glycolysis and activation of RA-FLSs. Here, we identified that knockdown of USP5 in RA rats reduced synovial inflammation and glycolytic activity, as evidenced by decreased serum lactate levels and GLUT1 expression. In RA-FLSs, USP5 knockdown or treatment with 2-DG reduced cell proliferation, migration, invasion, cytokine production, and glycolysis, while increased apoptosis. Mechanistically, USP5 stabilized METTL14 by inhibiting its ubiquitination, while METTL14 enhanced the m A modification of GLUT1 mRNA, thereby increasing its expression. Furthermore, overexpression of METTL14 partially reversed the effects of USP5 knockdown on glycolysis and inflammatory activation in RA-FLSs. Additionally, knockdown of METTL14 inhibited RA-FLS glycolysis and inflammatory activation by downregulating GLUT1. Collectively, USP5 stabilized METTL14-mediated m A modification of GLUT1 by inhibiting the ubiquitination of METTL14, thereby enhancing glycolysis and inflammatory activation in RA-FLSs. These results suggest that the USP5/METTL14/GLUT1 axis could be a potential therapeutic target for RA.