CELSR3 is a prognostic marker in HNSCC and correlates with immune cell infiltration in the tumor microenvironment.

PURPOSE: To look at the diagnostic value of the CELSR receptor 3 (CELSR3) gene in head and neck squamous cell carcinoma (HNSCC) and its effect on tumor immune invasion, which is important for enhancing HNSCC treatment. METHODS: Several bioinformatics tools were employed to investigate CELSR3's putative oncogenic pathway in HNSCC, and datasets from The Tumor Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), Gene Expression Profile Interaction Analysis (GEPIA) and LinkedOmics were extracted and evaluated. CELSR3 has been linked to tumor immune cell infiltration, immunological checkpoints, and immune-related genes. CELSR3's putative roles were investigated using Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and pathway enrichment analysis. The expression level of CELSR3 in HNSCC tissues and cells was detected by RT-qPCR. The effects of CELSR3 on proliferation of HNSCC cells were detected by CCK-8 assay. RESULTS: CELSR3 was shown to be expressed differently in different types of cancer and normal tissues. CELSR3 gene expression was linked to pN-stage and pM-stage. Patients with high CELSR3 expression also have a well prognosis. CELSR3 expression was found to be an independent predictive factor for HNSCC in both univariate and multivariate Cox regression analyses. We discovered the functional network of CELSR3 in HNSCC using GO and KEGG analysis. CELSR3 expression levels were found to be favorably associated with immune cell infiltration levels. Furthermore, CELSR3 expression levels were significantly correlated with the expression levels of many immune molecules, such as MHC genes, immune activation genes, chemokine receptors, and chemokines. CELSR3 is highly expressed in HNSCC tissues and cells. CELSR3 overexpression significantly inhibited the proliferation of HNSCC cells. CELSR3 expression may affect the immune microenvironment and, as a result, the prognosis of HNSCC. CONCLUSION: CELSR3 expression is elevated in HNSCC tumor tissues, and high CELSR3 expression is associated with well prognosis, which inhibited the proliferation of NHSCC cells. CELSR3 has the potential to influence tumor formation by controlling tumor-infiltrating cells in the tumor microenvironment (TME). As a result, CELSR3 may have diagnostic significance in HNSCC.

SLA2 is a prognostic marker in HNSCC and correlates with immune cell infiltration in the tumor microenvironment.

PURPOSE: To investigate Src-like adaptor 2 gene (SLA2) expression in head and neck squamous cell carcinoma (HNSCC), its potential prognostic value, and its effect on immune cell infiltration. METHODS: Through a variety of bioinformatics analyses, we extracted and analyzed data sets from the Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), and Gene Expression Profile Interaction Analysis (GEPIA) to analyze the correlation between SLA2 and the prognosis, immune checkpoint, tumor microenvironment (TME) and immune cell infiltration of HNSCC, and to explore its potential oncogenic mechanism. To further explore the potential role of SLA2 in HNSCC by Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: SLA2 messenger ribonucleic acid (mRNA) levels were increased in HNSCC tumor tissues compared with normal tissues. In addition, we found that SLA2 may be an independent prognostic factor for HNSCC, and high SLA2 expression is associated with favorable prognosis in HNSCC. SLA2 expression was positively correlated with B cells, cluster of differentiation 8-positive T cells (CD8 + T cells), cluster of differentiation 4-positive T cells (CD4 + T cells), macrophages, neutrophil and dendritic cells infiltration. SLA2 has also been shown to co-express immune-related genes and immune checkpoints. Significant GO term analysis by Gene Set Enrichment Analysis (GSEA) indicated that genes correlated with SLA2 were located mainly in the side of membrane, receptor complex, secretory granule membrane, endocytic vesicle, membrane region, and endosome membrane, where they were involved in leukocyte cell-cell adhesion, response to interferon-gamma, and regulation of immune effector process. These related genes also served as antigen binding, cytokine receptor activity, phosphatidylinositol 3-kinase activity, peptide receptor activity, Src homology domain 3 (SH3) domain binding, and cytokine receptor binding. KEGG pathway analysis demonstrated that these genes related to SLA2 were mainly enriched in signal pathways, such as hematopoietic cell lineage, cell adhesion molecules (CAMs), natural killer cell mediated cytotoxicity, measles, and chemokine signaling pathway. CONCLUSIONS: SLA2 is increased in HNSCC, and high SLA2 expression is associated with favorable prognosis. SLA2 may affect tumor development by regulating tumor infiltrating cells in TME. SLA2 may be a potential target for immunotherapy.

Influence of Neostigmine on Early Postoperative Cognitive Dysfunction in Older Adult Patients Undergoing Noncardiac Surgery: A Double-Blind, Placebo-Controlled, Randomized Controlled Trial.

BACKGROUND: The goal of this study was to investigate the efficacy of neostigmine on postoperative cognitive dysfunction (POCD) and determine its effect on systematic markers of oxidative stress in older patients. METHODS: This double-blind placebo-controlled trial enrolled 118 elderly patients (≥65 years) undergoing noncardiac surgeries who were allocated to a neostigmine treatment group (0.04 mg/kg) or a placebo control group (normal saline) postoperatively. POCD was diagnosed if the Z -scores for the mini-mental state examination and the Montreal Cognitive Assessment were both ≤-1.96. Postoperative serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and brain-derived neurotrophic factor (BDNF) were also compared. Multivariable regression analysis with dose adjustment of atropine was used to demonstrate the influence of neostigmine on the incidence of POCD. RESULTS: Patients receiving neostigmine had a significantly reduced incidence of POCD compared to patients who were treated with placebo on the first day after surgery (-22%, 95% confidence interval [CI], -37 to -7), but not on the third (8%, 95% CI, -4 to 20) or seventh day after surgery (3%, 95% CI, -7 to 13). Postoperative plasma MDA levels were significantly lower ( P = .016), but SOD and BDNF levels were increased ( P = .036 and .013, respectively) in the neostigmine group compared to the control group on the first day after surgery. CONCLUSIONS: Neostigmine reduced POCD on the first day after noncardiac surgery in older patients. Neostigmine treatment inhibited oxidative stress and increased serum BDNF levels. There was no significant influence of neostigmine on POCD on the third or seventh day after surgery. The clinical influence of neostigmine on POCD should be further investigated.

Prediction of network pharmacology, molecular docking-based strategy, and vitro assays to determine potential pharmacological mechanism of Dioscoreae bulbiferae and Bruceae fructus against laryngocarcinoma.

BACKGROUND: Based on network pharmacology, molecular docking, and vitro assays, investigate the probable pharmacological mechanism of Dioscoreae bulbiferae and Bruceae fructus in the treatment of laryngocarcinoma. METHODS: The active components and targets of Dioscoreae bulbiferae and Bruceae fructus were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database. Targets linked with laryngocarcinoma were gathered from the GeneCards, DisGeNET, and DrugBank databases. The String database was utilized to build a protein-protein interaction network of common medication and illness targets, after which the core targets were filtered out. The Metascape database served for gene ontology enrichment and Kyoto encyclopedia of genes and genomes pathway analysis of common targets. AutoDock then performed molecular docking between the essential component and the vital target. To investigate the biological effects of diosbulbin B, we assessed the viability of laryngocarcinoma cells after diosbulbin B therapy using the Mahalanobis Taguchi system technique. Following that, we looked at how diosbulbin B affected colony formation after 14 days of culture of treated cells. Flow cytometry was utilized to detect apoptosis in order to examine the influence of diosbulbin B on laryngocarcinoma cell apoptosis. RESULTS: According to a study of the literature, the fundamental components of Dioscoreae bulbiferae and Bruceae fructus in the treatment of laryngocarcinoma include brusatol and diosbulbin B, which may operate on core targets such as cyclin D1, Cyclin Dependent Kinase Inhibitor 1A, and E2F Transcription Factor 1. The significant pathways discovered using Kyoto encyclopedia of genes and genomes enrichment analysis were the phosphoinositide 3-kinase-protein kinase B signaling route, the tumor necrosis factor signaling pathway, and so on. These pathways primarily influence the development and prognosis of laryngeal cancer by controlling cell growth, cell proliferation, angiogenesis, tumorigenesis, and metastasis. The molecular docking studies revealed that the affinity between the heart and crucial targets was robust. The results of vitro assays indicate that diosbulbin B suppressed Hep-2 cell activity in a concentration-dependent manner. Besides, diosbulbin B has powerful antiproliferative properties in Hep-2 cells. Flow cytometry results showed that diosbulbin B promoted laryngocarcinoma cell apoptosis in a concentration-dependent manner. CONCLUSION: The article delivered a preliminary discussion of the probable mechanism of Dioscoreae bulbiferae and Bruceae fructus in the treatment of laryngocarcinoma, which can serve as a theoretical basis and evidence for subsequent experimental investigation.

Relief of Extracellular Matrix Deposition Repression by Downregulation of IRF1-Mediated TWEAK/Fn14 Signaling in Keloids.

Keloids represent a fibrotic disorder characterized by the excessive deposition of extracellular matrix (ECM). However, the mechanisms through which ECM deposition in keloids is regulated remain elusive. In this study, we found that the expression of both TWEAK and its cognate receptor Fn14 was significantly downregulated in keloids and that TWEAK/Fn14 signaling repressed the expression of ECM-related genes in keloid fibroblasts. The IRF1 gene was essential for this repression, and the TWEAK/Fn14 downstream transcription factor p65 directly bound to the promoter of the IRF1 gene and induced its expression. Furthermore, in patients with keloid, the expression of TWEAK and Fn14 was negatively correlated with that of ECM genes and positively correlated with that of IRF1. These observations indicate that relief of TWEAK/Fn14/IRF1-mediated ECM deposition repression contributes to keloid pathogenesis, and the identified mechanism and related molecules provide potential targets for keloid treatment in the future.

Prediction of network pharmacology and molecular docking-based strategy to determine potential pharmacological mechanism of Liuwei Dihuang pill against tinnitus.

BACKGROUND: Liuwei Dihuang Pill is widely used to treat tinnitus in China. However, the underlying mechanism of Liuwei Dihuang Pill in treating tinnitus still remains unclear. OBJECTIVE: To explore the potential pharmacological mechanism of Liuwei Dihuang Pill in the treatment of tinnitus based on network pharmacology and molecular docking. METHODS: The active components of the Liuwei Dihuang Pill were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database. Cytoscape software was used to draw the active component-target network diagram of Liuwei Dihuang Pill, and obtain the core components. Then the corresponding targets were also obtained from the TCMSP database. Targets related to tinnitus were obtained from the GeneCards, DisGeNET, TTD and DrugBank databases. The String database was used to construct protein-protein interaction (PPI) network of common targets of drugs and diseases, then the core targets were screened out. The Annotation, Visualization and Integrated Discovery (DAVID) database was used for gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis of common targets. Finally, the molecular docking between the core component and the core target was carried out by AutoDock. RESULTS: The core components of Liuwei Dihuang Pill in the treatment of tinnitus including quercetin, stigmasterol, kaempferol, ß-sitosterol, tetrahydroalstonine, which may act on core targets such as STAT3, transcription factor AP-1 (JUN), tumor necrosis factor (TNF), interleukin-6 and MAPK3. HIF-1 signaling pathway, Influenza A, P53 signaling pathway, and Toll-like receptor signaling pathway play a role in anti-inflammatory, improving microcirculation in the blood-labyrinth barrier, increasing cochlear blood flow, and preventing hair cell damage. The molecular docking results showed that the affinity between core components and core targets was good. CONCLUSION: The potential mechanism of Liuwei Dihuang Pill in the treatment of tinnitus was preliminarily discussed in this study, which may provide a theoretical basis and evidence for further experimental research.

TSP1 promotes fibroblast proliferation and extracellular matrix deposition via the IL6/JAK2/STAT3 signalling pathway in keloids.

Keloids are benign fibroproliferative diseases with abnormally proliferated bulges beyond the edge of the skin lesions, and they are characterized by uncontrolled fibroblast proliferation and excessive extracellular matrix deposition in the dermis. However, the definite mechanisms that increase fibroblast proliferation and collagen deposition in keloids remain unclear. Thrombospondin 1 (TSP1) has been suggested to play an important role in wound healing and fibrotic disorders, but its role in keloids is unknown. In this study, we aimed to clarify the specific role of TSP1 in keloids and explore the potential mechanism. Our results demonstrated that TSP1 was highly expressed in keloid lesions compared to normal skin. Knockdown of TSP1 in keloid fibroblasts decreased cell proliferation and collagen I deposition. Exogenous TSP1 treatment increased cell proliferation and collagen I deposition in normal fibroblasts. We further investigated the underlying mechanism and found that TSP1 promoted fibroblast proliferation and extracellular matrix deposition by upregulating the IL6/JAK2/STAT3 pathway. Moreover, we verified that TSP1 expression was positively correlated with IL6/STAT3 signalling activity in keloids. Taken together, our findings indicate that TSP1 promotes keloid development via the IL6/JAK2/STAT3 signalling pathway and blocking TSP1 may represent a potential strategy for keloid therapy.

LncRNA CCAT1 facilitates the proliferation, invasion and migration of human laryngeal squamous cell carcinoma cells via the miR-218-5p/BMI1.

Long non-coding RNAs (LncRNAs) are vital in the treatment of laryngeal squamous cell carcinoma (LSCC). This study estimated the mechanism of lncRNA CCAT1 (CCAT1) in LSCC cells. The expression of CCAT1 in the human laryngeal mucosal epithelial cells (HLCs) and LSCC cells (Hep-2 and TU177) was detected. CCK-8 and Transwell assays were used to evaluate the cell proliferative, migrative, and invasive abilities, respectively. The subcellular localization of CCAT1 was verified by RNA-FISH and cytoplasmic isolation assays. The targeted relationship among CCAT1, miR-218-5p, and BMI1 was verified by dual-luciferase assay. Expressions of miR-218-5p and BMI1 were detected by RT-qPCR. Our results depicted that CCAT1 was highly-expressed in Hep-2 and TU177 cells. Silencing CCAT1 inhibited the proliferation, migration, and invasion of Hep-2 and TU177 cells. Mechanically, CCAT1 regulated the BMI1 expression by competitively binding to miR-218-5p as a competing endogenous RNA (ceRNA), and thus facilitated the growth of Hep-2 and TU177 cells. Downregulation of miR-218-5p or upregulation of BMI1 inhibited the inhibitory effect of silencing CCAT1 on Hep-2 and TU177 cell proliferation, invasion, and migration. In conclusion, our study elicited that lncRNA CCAT1 facilitated the proliferation, migration, and invasion of Hep-2 and TU177 cells by sponging miR-218-5p and regulating the downstream BMI1.

The effects of neostigmine on postoperative cognitive function and inflammatory factors in elderly patients - a randomized trial.

BACKGROUND: Postoperative cognitive dysfunction is a common postoperative complication in elderly patients. In elderly patients, the decline of organ function and neuromuscular junction function make them more sensitive to muscle relaxants. They are more likely to experience residual muscle relaxation after surgery, which may cause various adverse events. Neostigmine, a commonly used muscle relaxant antagonist, can reduce the expression of inflammatory factors, thereby reducing the pro-inflammatory response and neurodegeneration of the cerebral cortex and hippocampus after surgery. The study aimed at observing the effect of different doses of neostigmine on postoperative cognitive function and peripheral inflammatory factors in elderly patients. METHODS: One hundred thirty-two elderly patients who underwent a radical section of gastrointestinal cancer at First Affiliated Hospital of Dalian Medical University were divided into neostigmine and saline groups at a 2:1 ratio. Neostigmine was intravenously injected in the post-anesthesia care unit (PACU) according to the train-of-four ratio (TOFR) T4/T1. When TOFR was ≤0.5, 0.04 mg/kg neostigmine was administered, whereas when TOFR was > 0.5, 0.02 mg/kg neostigmine was injected. The main observation indexes were cognitive function, interleukin 1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) in peripheral blood at the different times before and after the surgery. Secondary observation indicators include the number of atropine injection, extubating time, PACU residence time, incidence of hypoxemia, hypercapnia, and postoperative nausea and vomiting in PACU, time of exhaustion, and length of hospitalization. RESULTS: The extubating and PACU times in 0.04 mg/kg and 0.02 mg/kg groups were significantly shorter than those in the control group (P < 0.001). The incidence of early postoperative cognitive decline in 0.04 mg/kg and 0.02 mg/kg groups was 10 and 15.7%, respectively, which were significantly lower than those in the control group (P = 0.013). CONCLUSION: In elderly patients, 0.02-0.04 mg/kg neostigmine could significantly reduce the incidence of early postoperative cognitive decline without affecting peripheral inflammatory factors. TRIAL REGISTRATION: Trial registration: Chinese Clinical Trial Registry, ChiCTR2000031739. Registered 8 April 2020 - Retrospectively registered, http://www.medresman.org.cn .

TRAF4 Promotes Fibroblast Proliferation in Keloids by Destabilizing p53 via Interacting with the Deubiquitinase USP10.

Keloids represent one extreme of aberrant dermal wound healing. One of the important characteristics of keloids is uncontrolled fibroblasts proliferation. However, the mechanism of excessive proliferation of fibroblasts in keloids remains elusive. In this study, we demonstrated that TRAF4 was highly expressed in keloid fibroblasts and promoted fibroproliferation. We investigated the underlying molecular mechanism and found that TRAF4 suppressed the p53 pathway independent of its E3 ubiquitin ligase activity. Specifically, TRAF4 interacted with the deubiquitinase USP10 and blocked the access of p53 to USP10, resulting in p53 destabilization. Knockdown of p53 rescued cell proliferation in TRAF4-knockdown keloid fibroblasts, suggesting that the regulation of proliferation by TRAF4 in keloids relied on p53. Furthermore, in keloid patient samples, TRAF4 expression was inversely correlated with p53-p21 signaling activity. These findings help to elucidate the mechanisms underlying keloid development and indicate that blocking TRAF4 could represent a potential strategy for keloid therapy in the future.

TNFRSF19 Inhibits TGFß Signaling through Interaction with TGFß Receptor Type I to Promote Tumorigenesis.

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFß receptor type I (TßRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TßRI in the cytoplasm, thereby blocking Smad2/3 association with TßRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFß, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFß response characterized by upregulation of Smad2/3 phosphorylation and TGFß target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFß activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFß.Significance:TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFß signaling pathway.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3469/F1.large.jpg Cancer Res; 78(13); 3469-83. ©2018 AACR.

Loss of MED12 Induces Tumor Dormancy in Human Epithelial Ovarian Cancer via Downregulation of EGFR.

A high rate of disease relapse makes epithelial ovarian cancer (EOC) the leading cause of death among all gynecologic malignancies. These relapses are often due to tumor dormancy. Here we identify the RNA polymerase II transcriptional mediator subunit 12 (MED12) as an important molecular regulator of tumor dormancy. MED12 knockout (KO) induced dormancy of EOC cells in vitro and in vivo, and microarray analysis showed that MED12 KO decreased expression of EGFR. Restoration of EGFR expression in MED12 KO cells restored proliferation. Additionally, MED12 bound to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with EGFR expression in EOC patient samples. Clinical data demonstrated that chemotherapy-resistant patients expressed lower levels of MED12 compared with responsive patients. Overall, our data show that MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.Significance: MED12 is identified as a novel, important regulator of tumor dormancy in human ovarian cancer. Cancer Res; 78(13); 3532-43. ©2018 AACR.

A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis.

Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC.

Unconjugated Bilirubin Is a Novel Prognostic Biomarker for Nasopharyngeal Carcinoma and Inhibits Its Metastasis via Antioxidation Activity.

Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis-generated UCB cutoff point for DMFS was 9.7 µmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280-0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention.

NOP14 suppresses breast cancer progression by inhibiting NRIP1/Wnt/ß-catenin pathway.

NOP14, which is functionally conserved among eukaryotes, has been implicated in cancer development. Here, we show that NOP14 is poorly expressed in breast cancer cells and invasive breast cancer tissues. In vivo and in vitro studies indicated that NOP14 suppressed the tumorigenesis and metastasis of breast cancer cells. Further investigations revealed that NOP14 enhanced ERα expression and inhibited the Wnt/ß-catenin pathway by up-regulating NRIP1 expression. Survival analysis indicated that low NOP14 expression was significantly associated with poor overall survival (P = 0.0006) and disease-free survival (P = 0.0007), suggesting that NOP14 is a potential prognostic factor in breast cancer. Taken together, our findings reveal that NOP14 may suppress breast cancer progression and provide new insights into the development of targeted therapeutic agents for breast cancer.

Monoacylglycerol lipase promotes metastases in nasopharyngeal carcinoma.

Monoacylglycerol lipase (MAGL) is a serine hydrolase that hydrolyzes monoacylglycerides into free fatty acids and glycerol. It has recently been found to be involved in cancer progression through the free fatty acid or endocannabinoid network after studies on its function in the endocannabinoid system. Here, we determined a role for MAGL in nasopharyngeal carcinoma (NPC), which is known for its high metastatic potential. Among the different NPC cells we tested, MAGL was highly expressed in high metastatic NPC cells, whereas low metastatic potential NPC cells exhibited lower expression of MAGL. Overexpression of MAGL in low metastatic NPC cells enhanced their motile behavior and metastatic capacity in vivo. Conversely, knockdown of MAGL reduced the motility of highly metastatic cells, reducing their metastatic capacity in vivo. Growth rate was not influenced by MAGL in either high or low metastatic cells. MAGL expression was associated with the epithelial-mesenchymal transition (EMT) proteins, such as E-cadherin, vimentin and Snail. It was also related to the sidepopulation (SP) of NPC cells. Our findings establish that MAGL promotes metastases in NPC through EMT, and it may serve as a target for the prevention of NPC metastases.

Nigericin selectively targets cancer stem cells in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is prevalent in southern China, northern Africa, and Alaska. The prognosis for NPC patients at early stage is good, while it is poor for patients at late stages. Cancer stem cells (CSCs) have been proposed to be associated with tumor initiation, relapse and metastasis, and the poor prognosis of NPC likely results from residual CSCs after therapy. Study on the therapy targeting CSCs in NPC remains poor, though it received intensive attentions in other cancers. Here, we used NPC cell lines with high and low proportion of CSCs as models to explore the effect of nigericin, an antibiotic, on CSCs. We found that nigericin could selectively target CSCs and sensitize CSCs in NPC to the widely used clinical drug cisplatin both in vitro and in vivo. Moreover, downregulation of the polycomb group protein Bmi-1 may contribute to the inhibitory effect of nigericin on CSCs. Furthermore, by using the in vitro NPC cell models, we found that nigericin could significantly decrease the migration and invasion abilities, which are known to be associated with CSCs. Taken together, our results suggest that nigericin can selectively target CSCs in NPC, which could be a candidate CSCs targeting drug for clinical evaluation.