IKBKE promotes the ZEB2-mediated EMT process by phosphorylating HMGA1a in glioblastoma.

IKBKE (Inhibitor of Nuclear Factor Kappa-B Kinase Subunit Epsilon) is an important oncogenic protein in a variety of tumors, which can promote tumor growth, proliferation, invasion and drug resistance, and plays a critical regulatory role in the occurrence and progression of malignant tumors. HMGA1a (High Mobility Group AT-hook 1a) functions as a cofactor for proper transcriptional regulation and is highly expressed in multiple types of tumors. ZEB2 (Zinc finger E-box Binding homeobox 2) exerts active functions in epithelial mesenchymal transformation (EMT). In our current study, we confirmed that IKBKE can increase the proliferation, invasion and migration of glioblastoma cells. We then found that IKBKE can phosphorylate HMGA1a at Ser 36 and/or Ser 44 sites and inhibit the degradation process of HMGA1a, and regulate the nuclear translocation of HMGA1a. Crucially, we observed that HMGA1a can regulate ZEB2 gene expression by interacting with ZEB2 promoter region. Hence, HMGA1a was found to promote the ZEB2-related metastasis. Consequently, we demonstrated that IKBKE can exert its oncogenic functions via the IKBKE/HMGA1a/ZEB2 signalling axis, and IKBKE may be a prominent biomarker for the treatment of glioblastoma in the future.

Case report: Trigeminal neuralgia misdiagnosed as glossopharyngeal neuralgia.

Background: Trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GPN) are cranial nerve neuralgias with the same clinical manifestations, pathological features, and trigger factors; their affected sites are adjacent. Performing a magnetic resonance imaging (MRI) examination alone can easily lead to a misdiagnosis. Case presentation: A 72-year-old man had visited another hospital with severe left-sided tongue pain. On MRI, vascular compression of the glossopharyngeal nerve had been visible, with unclear evidence of trigeminal nerve involvement. He had been diagnosed with left-sided GPN and underwent microvascular decompression (MVD) of the left glossopharyngeal nerve. However, no improvement was observed after surgery. During a second surgery at our hospital, MVD of the trigeminal nerve was performed, and the trigeminal nerve was fully explored and separated. The patient's pain resolved after surgery. Ultimately, the patient was definitively diagnosed with left-sided TN. Discussion and conclusion: MVD is currently the most efficacious surgical option for treating cranial nerve neuralgia. To select patients for MVD, having an MRI criteria for identifying true neurovascular compression will be helpful. However, clinicians should focus more on a patient's clinical symptoms and not rely solely on MRI findings. This patient's case can help clinicians distinguish between TN and GPN, improve the understanding of these diseases, avoid misdiagnosis, and reduce the possibility of secondary damage.

Amlexanox Enhances Temozolomide-Induced Antitumor Effects in Human Glioblastoma Cells by Inhibiting IKBKE and the Akt-mTOR Signaling Pathway.

Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of IKBKE, for GBM. We found that the combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration, and invasion in primary glioma cells and in the human glioma cell line, U87 MG. As expected, TMZ enhanced the expression of p-AMPK and amlexanox led to the reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that compared to other groups treated with each component alone, TMZ combined with amlexanox effectively reversed the TMZ-induced activation of Akt and inhibited the phosphorylation of mTOR. In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. These results suggest that amlexanox sensitized the primary glioma cells and U87 MG cells to TMZ at least partially through the suppression of IKBKE activation and the attenuation of TMZ-induced Akt activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

MicroRNA­301a/ZNRF3/wnt/ß­catenin signal regulatory crosstalk mediates glioma progression.

MicroRNA (miR)­mediated mRNA and multiple signaling pathway dysregulations have been extensively implicated in several cancer types, including gliomas. Although previous studies have reported that miR­301a acts as an oncogene, the underlying mechanisms of miR­301a in the initiation and progression of glioma remain unknown. The present study aimed to investigate the involvement of miR­301a­mediated signaling pathway dysregulation in glioma. The results identified that miR­301a was significantly upregulated in gliomas and was associated with a poor prognosis based on The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Moreover, zinc and ring finger 3 (ZNRF3) exerted a critical role in the miR­301a­mediated effects on the malignant phenotype, such as by affecting proliferation and apoptosis. Mechanistically, the TOP/FOP luciferase assay, western blotting and immunofluorescence results demonstrated that miR­301a knockdown inhibited the wnt/ß­catenin signaling pathway, at least partially via ZNRF3, while ZNRF3 was a direct functional target of miR­301a, as indicated by luciferase reporter assay and western blot analysis. Furthermore, ZNRF3 could in turn repress miR­301a expression, which was dependent on the wnt pathway. Collectively, the present study identified a novel miR­301a/ZNRF3/wnt/ß­catenin signaling feedback loop that serves critical roles in glioma tumorigenesis, and that may represent a potential therapeutic target.

MicroRNA­422a functions as a tumor suppressor in glioma by regulating the Wnt/ß­catenin signaling pathway via RPN2.

MicroRNAs (miRs), which act as crucial regulators of oncogenes and tumor suppressors, have been confirmed to play a significant role in the initiation and progression of various malignancies, including glioma. The present study analyzed the expression and roles of miR­422a in glioma, and reverse transcription­quantitative PCR confirmed that miR­422a expression was significantly lower in glioblastoma multiforme (GBM) samples and cell lines compared with the low­grade glioma samples and the H4 cell line, respectively. miR­422a overexpression suppressed proliferation and invasion, and induced apoptosis in LN229 and U87 cell lines. Luciferase reporter assay, western blotting and RNA immunoprecipitation analysis revealed that ribophorin II (RPN2) is a direct functional target of miR­422a. Additionally, the overexpression of RPN2 partially reversed the miR­422a­mediated inhibitory effect on the malignant phenotype. Mechanistic investigation demonstrated that the upregulation of miR­422a inhibited ß­catenin/transcription factor 4 transcriptional activity, at least partially through RPN2, as indicated by in vitro and in vivo experiments. Furthermore, RPN2 expression was inversely correlated with miR­422a expression in GBM specimens and predicted patient survival in the Chinese Glioma Genome Atlas, UALCAN, Gene Expression Profiling Interactive Analysis databases. In conclusion, the present data reveal a new miR­422a/RPN2/Wnt/ß­catenin signaling axis that plays critical roles in glioma tumorigenesis, and it represents a potential therapeutic target for GBM.

RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/ß-catenin signaling pathway.

Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed ß-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3ß (GSK-3ß). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed ß-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/ß-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

Can we predict response to vagus nerve stimulation in intractable epilepsy.

BACKGROUND: Since vagus nerve stimulation (VNS) was approved by the Food and Drug Administration (FDA). A number of studies show that VNS was effective to reduce seizure frequency. However, there was still some patients treated with VNS having poor or even no clinical effect. OBJECTIVES: The purpose of the present review was to identify factors predicting the effect of VNS therapy and to select patients suitable for VNS treatment. METHOD: PubMed and Medline was searched with this terms "epilepsy," "vagus nerve stimulation," "vagal nerve stimulation," "VNS," "intractable," and "refractory".We selected studies by predefining inclusion and exclusion criteria. RESULTS: the effectiveness of VNA was confirmed by a number of studies. We find many studies exploring the predictive factors to VNS. However there was no any study finding factors correlating clearly with the outcome of VNS. Although, we find these factors, such as post-traumatic epilepsy, temporal lobe epilepsy and focal interictal epileptiform discharges (IEDs), were favorable for the treatment of VNS, while comprehensive IEDs and neuronal migration disorders were indicative of the poor effect. Also, temporal lobe epilepsy was generally effectively controlled by this therapy and yougers seemed to get more benefit from VNS. Additionally, other indexes, such as cytokine profile, slow cortical potential (SCP) shift, preoperative heart rate variability (HRV), EEG reactivity and connectomic profiling, maybe predict the results of VNS. CONCLUSION: In summary, these conventional and other new factors should be analyzed further by more science and rigorous experimental design to identify the clear correlation with the outcome of VNS therapy.