Abstract
Background
The resistance to radiotherapy remains a major obstacle that limits the efficacy of radiotherapy in non-small cell lung cancer (NSCLC). This study aims to illustrate the molecular ...mechanism underlying the role of LINC00665 in the radiosensitivity of NSCLC, which involves ubiquitin C-terminal hydrolase L3 (UCHL3).
Methods and results
The expression of UCHL3 was determined in clinical tissue samples collected from NSCLC patients and NSCLC cell lines. We found that UCHL3 overexpression occurred in both NSCLC tissues and cells, associated with poor prognosis in NSCLC patients. Mechanistically, UCHL3 stabilized aryl hydrocarbon receptor (AhR) protein through deubiquitination, thereby promoting PD-L1 expression. UCHL3 reduced the radiosensitivity of NSCLC cells by stabilizing AhR protein. Upstream microRNAs (miRNAs) and lncRNAs of UCHL3 were predicted by microarray profiling and validated by functional experiments. LINC00665 functioned as a sponge of miR-582-5p and thus up-regulated the expression of the miR-582-5p target UCHL3. Gain- and loss- of function assays were performed to assess the effects of LINC00665, UCHL3 and miR-582-5p on the in vitro cell malignant behaviors and immune escape as well as on the in vivo tumor growth. Silencing LINC00665 or overexpressing miR-582-5p enhanced the sensitivity of NSCLC cells to radiotherapy. LINC00665 augmented the immune escape of NSCLC cells in vitro and in vivo through stabilizing AhR protein via the miR-582-5p/UCHL3 axis.
Conclusions
Overall, LINC00665 reduced the radiosensitivity of NSCLC cells via stabilization of AhR through the miR-582-5p/UCHL3 axis.
MicroRNAs play significant roles in various malignancies, with breast cancer (BC) being no exception. Consequently, we explored the functional mechanism of miR-135 in the progression of BC. In total, ...55 pairs of BC and matched adjacent normal tissues were clinically collected from patients, followed by quantification of miR-135 and zinc finger protein 217 (ZNF217) expression patterns in BC tissues and cells. Accordingly, high ZNF217 expression and low miR-135 expression levels were identified in BC tissues and cells. Subsequently, the expressions of miR-135 and ZNF217 were altered to evaluate their effects on BC cell migration, invasion and EMT initiation. It was found that when ZNF217 was silenced or miR-135 was elevated, BC cell malignant behaviors were significantly inhibited, which was reproduced in nude mice for in vivo evidence. Furthermore, dual-luciferase reporter gene assay revealed the presence of direct binding between miR-135 and ZNF217. Subsequent co-immunoprecipitation, methylated-RNA binding protein immunoprecipitation and photoactivatable ribonucleoside enhanced-crosslinking and immunoprecipitation assays further revealed that ZNF217 could upregulate NANOG by reducing N6-methyladenosine levels via methyltransferase-like 13 (METTL3). Collectively, our findings highlighted the role of the miR-135/ZNF217/METTL3/NANOG axis in the progression of BC, emphasizing potential therapeutic targets ZNF217 silencing and miR-135 upregulation in preventing or treating BC.
Cancer cells reprogram their energy metabolic system from the mitochondrial oxidative phosphorylation (OXPHOS) pathway to a glucose-dependent aerobic glycolysis pathway. This metabolic reprogramming ...phenomenon is known as the Warburg effect, a significant hallmark of cancer. However, the detailed mechanisms underlying this event or triggering this reprogramming remain largely unclear. Here, we found that histone H2B monoubiquitination (H2Bub1) negatively regulates the Warburg effect and tumorigenesis in human lung cancer cells (H1299 and A549 cell lines) likely through controlling the expression of multiple mitochondrial respiratory genes, which are essential for OXPHOS. Moreover, our work also suggested that pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, can directly interact with H2B in vivo and in vitro and negatively regulate the level of H2Bub1. The inhibition of cell proliferation and nude mice xenograft of human lung cancer cells induced by PKM2 knockdown can be partially rescued through lowering H2Bub1 levels, which indicates that the oncogenic function of PKM2 is achieved, at least partially, through the control of H2Bub1. Furthermore, PKM2 and H2Bub1 levels are negatively correlated in cancer specimens. Therefore, these findings not only provide a novel mechanism triggering the Warburg effect that is mediated through an epigenetic pathway (H2Bub1) but also reveal a novel metabolic regulator (PKM2) for the epigenetic mark H2Bub1. Thus, the PKM2-H2Bub1 axis may become a promising cancer therapeutic target.
Aims
This study aimed to identify the clinical profiles of cervical spondylosis‐related internal jugular vein stenosis (IJVS) comprehensively.
Methods
A total of 46 patients, who were diagnosed as ...IJVS induced by cervical spondylotic compression were recruited. The clinical manifestations and imaging features of IJVS were presented particularly in this study.
Results
Vascular stenosis was present in 69 out of the 92 internal jugular veins, in which, 50.7% (35/69) of the stenotic vessels were compressed by the transverse process of C1, and 44.9% (31/69) by the transverse process of C1 combined with the styloid process. The transverse process of C1 compression was more common in unilateral IJVS (69.6% vs 41.3%, P = 0.027) while the transverse process of C1 combined with the styloid process compression had a higher propensity to occur in bilateral IJVS (52.2% vs 30.4%, P = 0.087). A representative case underwent the resection of the elongated left lateral mass of C1 and styloid process. His symptoms were ameliorated obviously at 6‐month follow‐up.
Conclusions
This study proposes cervical spondylotic internal jugular venous compression syndrome as a brand‐new cervical spondylotic subtype. A better understanding of this disease entity can be of great relevance to clinicians in making a proper diagnosis.
Summary
Extracranial venous abnormalities, especially jugular venous outflow disturbance, were originally viewed as nonpathological phenomena due to a lack of realization and exploration of their ...feature and clinical significance. The etiology and pathogenesis are still unclear, whereas a couple of causal factors have been conjectured. The clinical presentation of this condition is highly variable, ranging from insidious to symptomatic, such as headaches, dizziness, pulsatile tinnitus, visual impairment, sleep disturbance, and neck discomfort or pain. Standard diagnostic criteria are not available, and current diagnosis largely depends on a combinatory use of imaging modalities. Although few researches have been conducted to gain evidence‐based therapeutic approach, several recent advances indicate that intravenous angioplasty in combination with stenting implantation may be a safe and efficient way to restore normal blood circulation, alleviate the discomfort symptoms, and enhance patients’ quality of life. In addition, surgical removal of structures that constrain the internal jugular vein may serve as an alternative or adjunctive management when endovascular intervention is not feasible. Notably, discussion on every aspect of this newly recognized disease entity is in the infant stage and efforts with more rigorous designed, randomized controlled studies in attempt to identify the pathophysiology, diagnostic criteria, and effective approaches to its treatment will provide a profound insight into this issue.
Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke ...pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gamma‐aminobutyric acid (GABA) receptors (GABAB) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild‐type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABAB in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygen‐glucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABAB interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an interaction with GABAB receptors. GABAB activation using baclofen further reduced OGD‐induced neuron damage in culture and stroke outcomes of MCAO, relative to Shrm4 alone. Taken together, Shrm4‐mediated GABAB activation confers neuroprotection by reducing neuronal autophagy in acute ischemic stroke.
Lung cancer is a type of malignant tumor with high morbidity and mortality. Due to its complicated etiology and clinical manifestations, no significant therapeutic advance has been made. Lung ...squamous cell carcinoma (LSCC) is the most common type of lung cancer. To combat this disease, novel therapeutic targets are badly requirement. ASPM (Abnormal spindle-like microcephaly-associated protein) is involved in multiple cellular or developmental processes, such as neurogenesis and brain growth. ASPM is also reported widely expressed in multiple tumor tissues and involved in the development and progression of several cancers including lung cancer. However, the potential role on ASPM on LSCC is still unclear. In this study, we reported that ASPM was related to the poor prognosis of patients with lung squamous cell carcinoma. Our results further showed that ASPM depletion dramatically inhibited the proliferation of LSCC cells, consistent with the obviously decreased of cyclin D1(CCND1) and cyclin dependent kinases 4 (CDK4) expression. In vivo assays further confirmed ASPM ablation markedly blocked tumor growth in vivo compared with control. In addition, a co-expression was found between ASPM and CDK4 in human tumor tissues. Taken together, our data provides strong evidence that ASPM promotes lung squamous cell carcinoma proliferation in vitro and in vivo, and indicates its potential role as a LSCC therapeutic target.
Summary
Aims
The objective of this study was to evaluate cerebral venous recanalization with magnetic resonance black‐blood thrombus imaging (MRBTI) in patients with cerebral venous thrombosis (CVT) ...who underwent batroxobin treatment in combination with anticoagulation.
Methods
A total of 31 CVT patients were enrolled in this real‐world registry study. The patients were divided into batroxobin (n = 21) and control groups (n = 10). In addition to the same standard anticoagulation as in the control group, patients in the batroxobin group underwent intravenous batroxobin for a total of three times.
Results
In the batroxobin group compared with the control group, we found better odds of recanalization degree adjusted OR (95%CI) of 8.10 (1.61‐40.7) and segment‐stenosis attenuation adjusted OR (95%CI) of 4.48 (1.69‐11.9) with batroxobin treatment. We further noted a higher ratio of patients with the attenuation of stenosis adjusted OR (95%CI) of 26.4 (1.10‐635); as well as a higher ratio of segments with stenosis reversion adjusted OR (95%CI) of 4.52 (1.48‐13.8). However, neurological deficits between the two groups showed no statistical difference at 90‐day follow‐up (P > 0.05).
Conclusions
Batroxobin may promote venous sinus recanalization and attenuate CVT‐induced stenosis. Further randomized study of this promising drug may be warranted to better delineate the amount of benefit.
Radioresistance is a major challenge in the use of radiotherapy for the treatment of lung cancer while microRNAs (miRs) have been reported to participate in multiple essential cellular processes ...including radiosensitization. This study was conducted with the main objective of investigating the potential role of miR-320a in radioresistance of non-small cell lung cancer (NSCLC) via the possible mechanism related to HIF1α, KDM5B, and PTEN.
Firstly, NSCLC radiosensitivity-related microarray dataset GSE112374 was obtained. Then, the expression of miR-320a, HIF1α, KDM5B, and PTEN was detected in the collected clinical NSCLC samples, followed by Pearson's correlation analysis. Subsequently, ChIP assay was conducted to determine the content of the PTEN promoter fragment enriched by the IgG antibody and H3K4me3 antibody. Finally, a series of
and
assays were performed in order to evaluate the effects of miR-320a on radioresistance of NSCLC with the involvement of HIF1α, KDM5B, and PTEN.
The microarray dataset GSE112374 presented with a high expression of miR-320a in NSCLC radiosensitivity samples, which was further confirmed in our clinical samples with the use of reverse transcription-quantitative polymerase chain reaction. Moreover, miR-320a negatively targeted HIF1α, inhibiting radioresistance of NSCLC. Interestingly, miR-320a suppressed the expression of KDM5B, and KDM5B was found to enhance the radioresistance of NSCLC through the downregulation of PTEN expression. The inhibition of miR-320a in radioresistance of NSCLC was also reproduced by
assay.
Taken together, our findings were suggestive of the inhibitory effect of miR-320a on radioresistance of NSCLC through HIF1α-suppression mediated methylation of PTEN.
Background Several studies suggest that cyclooxygenase-2 （COX-2） contributes to the delayed progression of ischemic brain damage. This study was designed to investigate whether COX-2 inhibition with ...parecoxib reduces focal cerebral ischemia/eperfusion injury in rats. Methods Ninety male Sprague-Dawley rats were randomly assigned to three groups： the sham group, ischemia/reperfusion （I/R） group and parecoxib group. The parecoxib group received 4 mg/kg of parecoxib intravenously via the vena dorsalis penis 15 minutes before ischemia and again at 12 hours after ischemia. The neurological deficit scores （NDSs） were evaluated at 24 and 72 hours after reperfusion. The rats then were euthanized. Brains were removed and processed for hematoxylin and eosin staining, Nissl staining, and measurements of high mobility group Box 1 protein （HMGB1） and tumor necrosis factor-α （TNF-α） levels. Infarct volume was assessed with 2,3,5-triphenyltetrazolium chloride （TTC） staining. Results The rats in the I/R group had lower NDSs （P 〈0.05）, larger infarct volume （P 〈0.05）, lower HMGB1 levels （P 〈0.05）, and higher TNF-α levels （P 〈0.05） compared with those in the sham group. Parecoxib administration significantly improved NDSs, reduced infarct volume, and decreased HMGB1 and TNF-α levels （P 〈0.05）. Conclusions Pretreatment with intravenous parecoxib was neuroprotective. Its effects may be associated with the attenuation of inflammatory reaction and the inhibition of inflammatory mediators.
PDF
