Normal Nasopharyngeal Tissues Research Articles

Heterogeneous nuclear ribonucleoprotein K is a potential target for enhancing the chemosensitivity of nasopharyngeal carcinoma.

The resistance of tumor cells to chemotherapy drugs is a critical determinant in the recurrence and metastasis of nasopharyngeal carcinoma (NPC). Therefore, it is crucial to identify effective biotargets that can enhance the sensitivity of NPC cells to chemotherapy drugs. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) plays a central role in regulating chemotherapy resistance across various tumor types. However, its specific function in NPC cells remains unclear. This study reveals that hnRNPK is overexpressed in NPC tissues while weakly expressed in normal nasopharyngeal tissues. The expression level of hnRNPK is negatively associated with NPC patient survival. Importantly, hnRNPK is a key inducer of chemotherapy resistance in NPC, as evidenced by the significant increase in NPC cell sensitivity to cisplatin following hnRNPK knockdown. Mechanistically, hnRNPK induces chemotherapy resistance in NPC cells by suppressing the activation of the Akt/caspase 3 pathway. In NPC tumor-bearing mice, hnRNPK knockdown enhances the efficacy of cisplatin chemotherapy. Consequently, this work identifies a potential target for enhancing the sensitivity of NPC cells to chemotherapy.

The effect of interleukin-33 expression on prognosis in patients with nasopharyngeal carcinoma

IntroductionInterleukin-33 (IL-33) is a newly defined inflammatory cytokine that is a member of the interleukin-1 (IL-1) gene family. This cytokine is expressed in structural cells, such as the vascular endothelium, bronchial epithelial cells, keratinocytes, epithelial cells of the stomach, and fibroblastic reticular cells of lymphoid tissues. Several studies suggest that IL-33 plays a role in head-and-neck cancer. The aim of this study was to retrospectively examine IL-33 expression in nasopharyngeal carcinoma (NPC) and to evaluate its relationship between clinicopathological characteristics and prognosis. MethodsIn this monocentric, retrospective analysis, the data of 43 cases diagnosed with primary NPC and 20 cases with normal nasopharyngeal tissue (diagnosed between 2014 and 2020) were evaluated regarding the relationship between the immunohistochemically analyzed IL-33 expression status and corresponding clinicopathological parameters. ResultsThe mean age was 56.9 years. The majority (67.4%) of the patients had an early tumor stage (T1–T2). IL-33 expression was positive in 56% of the cases. The five-year overall survival rate was 77% for all patients, 90% for the patients with positive IL-33 expression, and 55% for those without IL-33 expression (p = 0.008, univariate analysis). In multivariate analysis, IL-33 expression was shown to be the only independent prognostic marker for nasopharyngeal carcinoma (p = 0.014). ConclusionThis retrospective study showed that IL-33 expression could be considered an independent factor affecting positively prognosis in NPC.

Network pharmacology and biological verification of morusin's therapeutic mechanisms in inhibiting nasopharyngeal carcinoma growth.

Nasopharyngeal carcinoma (NPC) presents a significant therapeutic challenge due to its aggressive nature and limited treatment options. Although morusin, a compound found in traditional Chinese medicines, exhibits significant tumor-inhibiting properties, its specific effects on NPC proliferation remain unclear. This study aims to elucidate the inhibitory effects of morusin on NPC survival and proliferation while exploring the underlying mechanisms through the utilization of network pharmacology, molecular docking, and experimental validation in vitro and in vivo. Network pharmacology analysis identified 117 potential targets of morusin against NPC, with 8 hub targets including AKT1, BCL2, CASP3, CTNNB1, ESR1, HSP90AA1, MMP9, STAT3, and the IL-17 signaling pathway. Further investigation of public data indicated that the expression levels of BLC2, CASP3, CTNNB1, HSP90AA1, and STAT3 in NPC tissue were significantly elevated compared to normal nasopharyngeal tissue. Docking studies exposed robust binding activity between morusin and key gene molecules. Additionally, biological assays demonstrated that morusin effectively inhibits NPC growth both in vivo and in vitro. Through a comprehensive investigation, this study identified the pharmacological mechanisms essential for morusin-induced inhibition of NPC growth by targeting multiple molecular targets and signaling pathways. These findings show the potential to contribute to the development of novel clinical agents for treating NPC.

Hypermethylated GPR135 gene expression is a favorable independent prognostic factor in nasopharyngeal carcinoma

PurposeTo investigate the methylation status and expression level of G protein-coupled receptor 135 (GPR135) in nasopharyngeal carcinoma (NPC) and determine its prognostic value.MethodsThe GPR135 methylation data of NPC and normal nasopharyngeal tissues were obtained from the Gene Expression Omnibus (GEO) GSE52068 dataset. The GPR135 promoter region methylation level in four normal nasopharyngeal epithelial tissues and eight NPC tissues was detected by bisulfite sequencing. GPR135 expression in NPC and normal nasopharyngeal tissue was obtained from the GEO GSE13597 dataset.The GPR135 mRNA expression levels in 13 NPC and 26 healthy control tissues were assessed with quantitative real-time PCR (qRT-PCR). The GPR135 expression level in 124 NPC tissue sections was analyzed by immunohistochemistry. The correlation between GPR135 expression and clinicopathological features was analyzed by a chi-square test. GPR135 expression in patients with NPC was evaluated by immunohistochemistry, and its influence on prognosis was assessed by Kaplan-Meier and Cox regression analyses.ResultsThe bisulfite sequencing demonstrated that the GPR135 promoter region was highly methylated in NPC tissues. The immunohistochemistry results revealed that patients with high GPR135 expression had better overall survival (hazard ratio [HR] = 0.177, 95% confidence interval [95%CI]: 0.072–0.437, P = 0.008), disease-free survival (HR = 0.4401, 95%CI: 0.222–0.871, P = 0.034), and local recurrence-free survival (HR = 0.307, 95%CI: 0.119–0.790, P = 0.046) than those with low GPR135 expression.ConclusionGPR135 is hypermethylated in NPC, where high GPR135 expression indicates a positive prognosis. Therefore, GPR135 might be a prognostic indicator.

Expression of cytoskeleton-associated protein 4 is associated with poor prognosis and metastasis in nasopharyngeal carcinoma.

Cytoskeleton-associated protein 4 (CKAP4) acts as a key transmembrane protein that connects the endoplasmic reticulum (ER) to microtubule dynamics. Researchers have not examined the roles of CKAP4 in nasopharyngeal carcinoma (NPC). The study aimed at evaluating the prognostic value and metastasis-regulating effect of CKAP4 in NPC. CKAP4 protein could be observed in 86.36% of 557 NPC specimens but not in normal nasopharyngeal epithelial tissue. According to immunoblot assays, NPC cell lines presented high CKAP4 expression relative to NP69 immortalized nasopharyngeal epithelial cells. Moreover, CKAP4 was highly expressed at the NPC tumor front and in matched liver, lung, and lymph node metastasis samples. Furthermore, high CKAP4 expression reported poor overall survival (OS) and presented a positive relevance to tumor (T) classification, recurrence, and metastasis. According to multivariate analysis, CKAP4 could independently and negatively predict patients' prognosis. Stable knockdown of CKAP4 expression in NPC cells inhibited cell migration, invasion and metastasis in vitro and in vivo. Moreover, CKAP4 promoted epithelial-mesenchymal transition (EMT) in NPC cells. CKAP4 knockdown was followed by the downregulation of the interstitial marker vimentin, and upregulation of the epithelial marker E-cadherin. In NPC tissues, high CKAP4 expression exhibited a positive relevance to vimentin expression and a negative relevance to E-cadherin expression. In conclusion, CKAP4 is an independent predictor of NPC, and CKAP4 might contribute NPC progression and metastasis, which may be involved in EMT with vimentin and E-cadherin.

Proteomics Profiling Reveals the Molecular Signatures and Potential Therapeutic Targets of Human Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC), a malignant tumor distinctly characterized by ethnic and geographic distribution, is highly prevalent in Southern China and Southeast Asia. However, the molecular mechanisms of NPC have not been fully revealed at the proteomic level. In this study, 30 primary NPC samples and 22 normal nasopharyngeal epithelial tissues were collected for proteomics analysis, and a relatively complete proteomics landscape of NPC was depicted for the first time. By combining differential expression analysis, differential co-expression analysis, and network analysis, potential biomarkers and therapeutic targets were identified. Some identified targets were verified by biological experiments. We found that 17-AAG, a specific inhibitor of the identified target heat shock protein 90 (HSP90), could be a potential therapeutic drug for NPC. Finally, consensus clustering identified two NPC subtypes with specific molecular features. The subtypes and the related molecules were verified by an independent data set and may have different progression-free survival. The results of this study provide a comprehensive understanding of the proteomics molecular signatures of NPC and provide new perspectives and inspiration for prognostic determination and treatment of NPC.

The valuable role of dynamic 18F FDG PET/CT-derived kinetic parameter [formula omitted] in patients with nasopharyngeal carcinoma prior to radiotherapy: A prospective study

Background and PurposeDynamic positron emission tomography/computed tomography (PET/CT) served the potential role of characterizing malignant foci. The main objective of this prospective study was to explore the advantage of dynamic PET/CT imaging in characterizing nasopharyngeal carcinoma (NPC). Methods and MaterialsPatients with probable head and neck disease underwent a local dynamic PET/CT scan followed by a whole-body static scan. Patlak analysis was used to generate parametric influx rate constant (Ki) images from 48 frames obtained from a dynamic PET/CT scan. By delineating the volumes-of-interest (VOIs) of: primary tumor (PT), lymph node (LN), and normal nasopharyngeal tissues (N), we acquired the corresponding Ki mean and SUVmean of each site respectively to perform the quantitative statistical analysis. ResultsQualified images of 71 patients with newly diagnosed NPC and 8 without nasopharyngeal malignant lesions were finally included. We found the correlations between Ki mean-PT and critical clinical features, including clinical stage (r = 0.368), T category (r = 0.643) and EBV-DNA copy status (r = 0.351), and Ki mean-PT differed within the group. SUVmean-PT showed correlations with clinical stage (r = 0.280) and T category (r = 0.472), but could hardly differ systematically within group of clinical features except T category. Ki mean-LN offered the positive correlations with N category (r = 0.294), M category (r = 0.238) and EBV-DNA copy status (r = 0.446), and differed within the group. In addition, Ki mean represented a sensitivity of 94.4 % and a specificity of 100 %, in distinguishing NPC from the non-NPC, when the cut-off was defined as 0.0106. When the cut-off of SUV being defined as 2.03, the sensitivity and specificity were both 100 %. ConclusionOur research confirmed Ki compared favorably to SUV in characterizing NPC and found that Ki can serve as an effective imaging marker of NPC.

Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evidence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the development of NPC. In particular, the EBV principal oncogene, latent membrane protein 1 (LMP1), is considered a key factor in inducing aberrant DNA methylation of several tumour suppressor genes in NPC, although the mechanism remains unclear. Herein, we comprehensively analysed the methylome data of Infinium BeadArray from 51 NPC and 52 normal nasopharyngeal tissues to identify LMP1-inducible methylation genes. Using hierarchical clustering analysis, we classified NPC into the high-methylation, low-methylation, and normal-like subgroups. We defined high-methylation genes as those that were methylated in the high-methylation subgroup only and common methylation genes as those that were methylated in both high- and low-methylation subgroups. Subsequently, we identified 715 LMP1-inducible methylation genes by observing the methylome data of the nasopharyngeal epithelial cell line with or without LMP1 expression. Because high-methylation genes were enriched with LMP1-inducible methylation genes, we extracted 95 high-methylation genes that overlapped with the LMP1-inducible methylation genes. Among them, we identified DERL3 as the most significantly methylated gene affected by LMP1 expression. DERL3 knockdown in cell lines resulted in significantly increased cell proliferation, migration, and invasion. Lower DERL3 expression was more frequently detected in the advanced T-stage NPC than in early T-stage NPC. These results indicate that DERL3 repression by DNA methylation contributes to NPC tumour progression.

Predicting AURKA as a novel therapeutic target for NPC: A comprehensive analysis based on bioinformatics and validation.

This study comprehensively explored the clinical function of Aurora kinase A (AURKA) gene in nasopharyngeal carcinoma (NPC) and analyzed its potential as a therapeutic target in cancer. Data were downloaded from GEO, STRING, GTEx, and CellMiner databases, and subjected to multiple bioinformatic analyses, including differential expression analysis, WCGNA, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), miRNA-hub gene regulatory network analysis, immune cell infiltration, and drug sensitivity analysis. In-depth analysis of AURKA gene expression in NPC and its corresponding clinicopathological features was performed to explore its potential as a therapeutic target. Moreover, AURKA gene expression in NPC was validated by qRT-PCR in 21 NPC tissues and 17 normal nasopharyngeal epithelial tissues. AURKA was highly expressed in NPC tissues. Enrichment analysis of AURKA and its co-expressed hub genes indicated their oncogenic role in NPC and their potential involvement in cancer-promoting processes through histone kinase activity and microtubule motility activity, cell cycle, and p53 signaling pathways. AURKA high expression group had greater infiltration of neutrophils, macrophages M2, and dendritic cells resting and less infiltration of T cells CD4+ naïve and T cells γδ. Drug susceptibility analysis found that dacarbazine, R-306465, vorinostat, and other antitumor drugs that act on the cell cycle were closely related to AURKA. qRT-PCR verified the high expression of AURKA in NPC tissues (p < 0.05). We confirmed upregulation of AURKA in NPC tissues. Our results support an oncogenic role of AURKA in the context of NPC, and indicate its potential role as a novel therapeutic target.

Function of AXL and molecular mechanisms in regulation of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignant tumor with unique geographical and ethnic distribution characteristics. NPC is mostly found in south China and Southeast Asia, and its treatment mainly depends on radiotherapy and chemotherapy. However, NPC is usually found in the late stage, and local recurrence and distant metastasis are common, leading to poor prognosis. The receptor tyrosine kinase AXL is up-regulated in various tumors and it is involved in tumor proliferation, migration, invasion, and other processes, which are associated with poor prognosis of tumors. This study aims to detect the expression of AXL in NPC cell lines and tissues, and to investigate its biological function of AXL and the underlying molecular mechanisms in regulation of NPC. The expression levels of AXL in normal nasopharyngeal epithelial tissues and NPC tissues were analyzed by GSE68799, GSE12452, and GSE53819 data sets based on Gene Expression Omnibus (GEO) database. The Cancer Genome Atlas (TCGA) database was used to analyze the relationship between AXL and prognosis of head and neck squamous cell carcinoma (HNSC). The indicators of prognosis included overall survival (OS), disease-free interval (DFI), disease-specific survival (DSS), and progression-free interval (PFI). Western blotting assay was used to detect the AXL protein expression levels in normal nasopharyngeal epithelial cell line and NPC cell lines. Immunohistochemical method was used to detect AXL expression levels in normal nasopharyngeal epithelial tissues and NPC tissues. Cell lines with stable AXL knockdown were established by infecting 5-8F and Fadu cells with lentivirus interference vector, and cell lines with stable AXL overexpression were established by infecting C666-1 and HK-1 cells with lentivirus expression vector. Real-time PCR and Western blotting were used to detect the efficiency of knockdown and overexpression in stable cell lines. The effects of AXL knockdown or overexpression on proliferation, migration, and invasion of NPC cells were detected by CCK-8, plate colony formation, and Transwell assays, and the effect of AXL knockdown on tumor growth in nude mice was detected by subcutaneous tumor formation assay. The sequence of AXL upstream 2.0 kb promoter region was obtained by UCSC online database. The PROMO online database was used to predict AXL transcription factors with 0% fault tolerance, and the JASPAR online database was used to predict the binding sites of ETS1 to AXL. Real-time PCR and Western blotting were used to detect the effect of ETS1 on AXL protein and mRNA expression. The AXL upstream 2.0 kb promoter region was divided into 8 fragments, each of which was 250 bp in length. Primers were designed for 8 fragments. The binding of ETS1 to AXL promoter region was detected by chromatin immuno-precipitation (ChIP) assay to determine the direct regulatory relationship between ETS1 and AXL. Rescue assay was used to determine whether ETS1 affected the proliferation, migration, and invasion of NPC cells through AXL. Bioinformatics analysis showed that AXL was highly expressed in NPC tissues (P<0.05), and AXL expression was positively correlated with OS, DFI, DSS, and PFI in HNSC patients. Western blotting and immunohistochemical results showed that AXL was highly expressed in NPC cell lines and tissues compared with the normal nasopharyngeal epithelial cell line and tissues. Real-time PCR and Western blotting results showed that knockdown and overexpression efficiency in the stable cell lines met the requirements of subsequent experiments. The results of CCK-8, plate colony formation, Transwell assays and subcutaneous tumor formation in nude mice showed that down-regulation of AXL significantly inhibited the proliferation, migration, invasion of NPC cells and tumor growth (all P<0.05), and the up-regulation of AXL significantly promoted the proliferation, migration, and invasion of NPC cells (all P<0.05).As predicted by PROMO and JASPAR online databases, ETS1 was a transcription factor of AXL and had multiple binding sites in the AXL promoter region. Real-time PCR and Western blotting results showed that knockdown or overexpression of ETS1 down-regulated or up-regulated AXL protein and mRNA expression levels. ChIP assay result showed that ETS1 bound to AXL promoter region and directly regulate AXL expression. Rescue assay showed that AXL rescued the effects of ETS1 on proliferation, migration and invasion of NPC cells (P<0.05). AXL is highly expressed in NPC cell lines and tissues, which can promote the malignant progression of NPC, and its expression is regulated by transcription factor ETS1.

Myocardin immunohistochemistry index is associated with clinical prognosis in nasopharyngeal carcinoma: a clinical practice-based cohort study

Purpose: Recent findings have implicated the role of myocardin re-expression in carcinogenesisHowever, the clinical functions of myocardin in nasopharyngeal carcinoma (NPC) is not known yet. The purpose for the cohort research was to investigate whether myocardin re-expression level may predict clinical prognosis in NPC patients.Methods: 148 NPC patients were recruited from September, 2005 to September, 2011 with median follow-up time of 4.5 years in a clinical practice setting. At study entry myocardin re-expression of these patients was determined using immunohistochemistry (IHC) and additional 20 normal nasopharyngeal tissues were included as control. Two-sample t-test was used to compare mean myocardin reexpression levels and Chi-square test was used for comparing tumour recurrence rate. Logistic regression analysis was used for tumour local control rate, and log-rank test, Kaplan-Meier estimates and Cox proportional hazard model for disease-free survival and overall survival.Results: Myocardin IHC index was significantly downregulated in NPC samples than in normalnasopharyngeal tissues (mean ± standard deviation, 61.2 ±31.5 vs. 109.9 ±73.6, P= 0.009). However, among NPC patients was observed a roughly V-shaped change of myocardin IHC index according to Tumour T-stage (P=0.067); meanwhile higher IHC level was associated with more tumour recurrence rate in NPC patients (High vs. Low: 21.6% vs. 8.1%; P=0.021). Logistic regression analysis equally showed high myocardin IHC level was an independent risk factor for local tumour control rate regardless of adjustments [High vs. Low: unadjusted Odds Ratio (OR) 0.320, 95% confidence interval (CI): 0.117 to 0.871; P=0.026]. Moreover, higher myocardin IHC level was associated with a marginal but not significant risk increase of disease-free survival [High vs. Low: adjusted Hazard Ratio (HR) 1.760, 95% CI: 0.981 to 3.158; log-rank: P=0.129]. A less obvious trend was observed with regard to overall survival [adjusted HR 1.409, 95% CI: 0.715 to 2.77; log-rank: P=0.745].Conclusion: The study results suggested that high myocardin IHC index level could be a potential clinically prognostic intermediate biomarker for tumour recurrence for NPC patients in routine practice. Large well-designed cohort studies involving IHC re-expression change over time is needed.

Differentially Expressed Genes in Nasopharyngeal Carcinoma Tissues and Their Correlation with Recurrence and Metastasis of Nasopharyngeal Carcinoma.

In this study, bioinformatics tools were used to identify key genes to study the molecular mechanism of nasopharyngeal carcinoma (NPC) development and to explore the correlation of these key genes with the recurrence and metastasis of NPC. The GSE61218 microarray dataset obtained from the Gene Expression Omnibus Database (GEO) was used. The limma R package was used to screen differentially expressed genes (DEGs) between NPC and normal nasopharyngeal (NP) tissues. KEGG functional enrichment was performed on these selected DEGs. Protein-protein interaction (PPI) networks were constructed using Cytoscape software to identify key node proteins. The NPC-metastasis microarray dataset GSE103611 was obtained from GEO to analyze the expression of DEGs in NPC metastasis. A total of 239 DEGs were identified. DEGs were mainly enriched in oocyte maturation-related pathways, cytokine-related pathways, cell cycle-related pathways, cancer-related pathways, and homologous recombination-related pathways. In addition, the top 10 nodes with the higher degree in the DEG PPI network were as follows: CDK1, CCNB2, BUB1, CCNA2, AURKB, BUB1B, MAD2L1, NDC80, BIRC5, and CENPF. The results indicated that DEGs may be involved in the pathogenesis of NPC by regulating cell cycle and mitosis, which can be used as molecular biomarkers for the diagnosis of NPC. In addition, we identified 87 DEGs with FC > 2 and P < 0.01 from the metastasis spectrum of NPC. The intersection gene between DEGs of NPC and normal NP tissue samples and those of the metastatic spectrum of NPC was identified to be VRK2. The expression of VRK2 in NPC samples was significantly higher than that in normal NP tissue, and similarly, VRK2 expression was significantly upregulated in metastatic samples compared with nonmetastatic samples (P < 0.05). Therefore, VRK2 may be a biomarker for predicting the metastasis of NPC patients after treatment.

Ceruloplasmin inhibits the proliferation, migration and invasion of nasopharyngeal carcinoma cells and is negatively regulated by miR-543

Background Ceruloplasmin (CP), recognized as a member of multicopper oxidase family, is related to the progression of diverse cancers in human beings. This study is designed to clarify the expression characteristics, biological function and related mechanism of CP in nasopharyngeal carcinoma (NPC). Methods CP expression in NPC tissues and cells was probed by quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and Western blot. After gain-of-function and loss-of-function models were established, cell counting kit-8 (CCK-8), Transwell and BrdU assays were employed to measure cell viability, migration and invasion. The targeting relationship between microRNA-543 (miR-543) and CP was verified by dual-luciferase reporter gene assay. Results As against normal nasopharyngeal epithelial tissues, CP expression was significantly lower in NPC tissues, which was associated with higher clinical stage and the short overall survival time. Compared with the control group, CP overexpression markedly restrained the growth, migration and invasion of NPC cells; knocking down CP had the opposite effect. MiR-543 directly targeted CP and negatively modulated its expression. Conclusion CP restrains the growth, migration and invasion of NPC cells and is negatively regulated by miR-543.

CircTMTC1 contributes to nasopharyngeal carcinoma progression through targeting miR-495-MET-eIF4G1 translational regulation axis

Nasopharyngeal carcinoma (NPC) is the most common primary malignancy arising from the epithelial cells of nasopharynx. CircTMTC1 is upregulated in NPC patients, but its role and molecular mechanism in NPC are unknown. Normal nasopharyngeal epithelium and tumor tissues were collected. The expression of circTMTC1, miR-495, MET/eIF4G1 pathway-related molecules were examined. Colony formation and transwell assays were used to assess cell proliferation, migration, and invasion. Cell apoptosis was analyzed by annexin V and propidium iodide (PI) staining. Gene interaction was examined by RNA immunoprecipitation (RIP) and luciferase activity assays. Subcutaneous and intravenous xenograft mouse models were established to analyze NPC growth and metastasis in vivo. CircTMTC1 was highly expressed and miR-495 was downregulated in NPC, which were associated with poor prognosis of NPC. Both circTMTC1 knockdown and miR-495 overexpression inhibited NPC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) and promoted cell apoptosis. CircTMTC1 directly targeted miR-495 to promote the expression of its downstream target gene MET. miR-495 knockdown enhanced the expression of c-Myc, Cyclin D1, and survivin and accelerated NPC cell proliferation, migration, invasion, and EMT through targeting MET and activating the MET-eIF4G1 axis. CircTMTC1 silence inhibited NPC growth and lung metastasis by targeting the miR-495-MET-eIF4G1 translational regulation axis in vivo. CircTMTC1 accelerates NPC progression through targeting miR-495 and consequently activating the MET-eIF4G1 translational regulation axis, suggesting potential therapeutic targets for NPC treatment.

Mesenchymal Stem Cells Inhibits Migration and Vasculogenic Mimicry in Nasopharyngeal Carcinoma Via Exosomal MiR-125a.

Vasculogenic mimicry (VM) is a kind of tumor vasculature providing blood supply for tumor growth, and the formation of VM is independent of vascular endothelial cells. Instead, VM structures are formed by differentiated tumor cells such as nasopharyngeal carcinoma cells. Recently, studies have shown that anti-angiogenic therapy failed to improve the overall survival for patients, namely, nasopharyngeal carcinoma patients. The existence of VM structure is probably one of the reasons for resistance for anti-angiogenic therapy. Therefore, it is important to study the mechanism for VM formation in nasopharyngeal carcinoma. In this study, the bioinformatic analysis revealed that microRNA-125a-3p (miR-125a) was highly expressed in normal nasopharyngeal epithelial tissue than in nasopharyngeal carcinoma. An in vitro study demonstrated that miR-125a plays an inhibitory role in nasopharyngeal carcinoma cell migration and VM formation, and further studies confirmed that TAZ is a direct downstream target for miR-125a. On this basis, we artificially engineered human mesenchymal stem cells (MSCs) to generate exosomes with high miR-125a expression. Treatment with these miR-125a-over-expressing exosomes attenuated the migration and VM formation in nasopharyngeal carcinoma cells. In addition, the inhibitory role of these exosomes on VM formation and migration in nasopharyngeal carcinoma was also confirmed in vivo. Overall, the current study shows that MSCs can be utilized to generate exosomes with high miR-125a level, which could be therapeutic nanoparticles targeting VM formation in nasopharyngeal carcinoma and used as a complement to anti-angiogenic therapy in the future.

Baseline Amide Proton Transfer Imaging at 3T Fails to Predict Early Response to Induction Chemotherapy in Nasopharyngeal Carcinoma.

BackgroundEarly identification of nasopharyngeal carcinoma (NPC) patients with high risk of failure to induction chemotherapy (IC) would facilitate prompt individualized treatment decisions and thus reduce toxicity and improve overall survival rate. This study aims to investigate the value of amide proton transfer (APT) imaging in predicting short-term response of NPC to IC and its potential correlation with well-established prognosis-related clinical characteristics.Methods and MaterialsA total of 80 pathologically confirmed NPC patients receiving pre-treatment APT imaging at 3T were retrospectively enrolled. Using asymmetry analysis, APT maps were calculated with mean (APTmean), 90th percentile (APT90) of APT signals in manually segmented NPC measured. APT values were compared among groups with different histopathological subtypes, clinical stages (namely, T, M, N, and overall stages), EBV-related indices (EBV-DNA), or responses to induction chemotherapy, using Mann–Whitney U test or Kruskal–Wallis H test.ResultsNPC showed significantly higher APTmean than normal nasopharyngeal tissues (1.81 ± 0.62% vs.1.32 ± 0.56%, P <0.001). APT signals showed no significant difference between undifferentiated and differentiated NPC subtypes groups, different EBV-DNA groups, or among T, N, M stages and overall clinical stages of II, III, IVA and IVB (all P >0.05). Similarly, baseline APT-related parameters did not differ significantly among different treatment response groups after IC, no matter if evaluated with RECIST criteria or sum volumetric regression ratio (SVRR) (all P >0.05).ConclusionNPC showed significantly stronger APT effect than normal nasopharyngeal tissue, facilitating NPC lesion detection and early identification. However, stationary baseline APT values exhibited no significant correlation with histologic subtypes, clinical stages and EBV-related indices, and showed limited value to predict short-term treatment response to IC.

Targeting ALDH1A1 to induce Necroptosis in Nasopharyngeal Carcinoma.

ALDH1A1 is one of the highly conserved isoenzymes of the aldehyde dehydrogenase family. It is mainly involved in the metabolism of intracellular aldehydes and forms transcriptional regulators, which are essential for growth and differentiation of normal cells. Overexpression of ALDH1A1 in many malignancies and cancer stem cells (CSCs) is closely associated with poor prognosis and promotes tumor aggressiveness and drug resistance during conventional cancer chemotherapy. In this study, we found that ALDH1A1 had tumor suppressor effects in BRCA, CESC, LIHC, Lung cancer, renal cell carcinoma and PAAD, but tumor-promoting effects in SKCM, GBM, THCA and BLCA. As for the nasopharyngeal carcinoma, ALDH1A1 mainly played a carcinogenic role. We found that although the expression of ALDH1A1 in NPC tissue was lower than that in normal nasopharyngeal mucosal tissue, it was upregulated in patients with higher clinical stages, and correlated with poor patient outcomes. Therefore, we further analyzed the main possible role of ALDH1A1 in NPC by taking GSE12452 dataset. The GSEA enrichment analysis showed that it could inhibit the necroptosis of nasopharyngeal carcinoma cells. Therefore, we used the targeted inhibitor NCT-501 and found that it could inhibit the proliferation and stem cell spheroidization of NPC cells, and induce necroptosis. This study explored the possible role of ALDH1A1 in various tumors and focused on its potential role as a target in NPC. Meanwhile, ALDH1A1 inhibitor preferentially has potential therapeutic value in NPC.

LACTB2 renders radioresistance by activating PINK1/Parkin-dependent mitophagy in nasopharyngeal carcinoma

Radiotherapy is a standard and conventional treatment strategy for nasopharyngeal carcinoma (NPC); however, radioresistance remains refractory to clinical outcomes. Understanding the molecular mechanism of radioresistance is crucial for advancing the efficacy of radiotherapy and improving the prognosis of NPC. In this study, β-lactamase-like-protein 2 (LACTB2) was identified as a potential biomarker for radioresistance using tandem mass tag proteomic analysis of NPC cells, gene chip analysis of NPC tissues, and differential gene analysis between NPC and normal nasopharyngeal tissues from the Gene Expression Omnibus database GSE68799. Meanwhile, LACTB2 levels were elevated in the serum of patients with NPC after radiotherapy. Inhibiting LACTB2 levels and mitophagy can sensitize NPC cells to ionizing radiation. In NPC cells, LACTB2 was augmented at the transcription and protein levels after radiation rather than nucleus-cytoplasm-mitochondria transposition to activate PTEN-induced kinase 1 (PINK1) and mitophagy. In addition, LACTB2 was first authenticated to co-locate with PINK1 by interacting with its N-terminal domain. Together, our findings indicate that overexpressed LACTB2 provoked PINK1-dependent mitophagy to promote radioresistance and thus might serve as a prognostic biomarker for NPC radiotherapy.

High-throughput chromosome conformation capture-based analysis of higher-order chromatin structure in nasopharyngeal carcinoma.

BackgroundFirstly, we aimed to compare the differences of higher-order chromatin structure between nasopharyngeal carcinoma (NPC) and normal nasopharyngeal tissues. The second objective was to analyze the specific chromatin interaction site of NPC and the NPC-related genes regulated by this interaction site.MethodsWe included 6 NPC patients and 6 healthy controls to obtain the sequencing results of highest-throughput chromosome conformation capture (Hi-C) technique, followed by further analysis of the specific chromatin interaction sites in NPC.ResultsWe found an abnormal ultra-long distance interaction site on the chromosome 7p in the CNE210 sample, which was caused by a fusion gene SEPT7P2-PSPH. Additionally, a significant interaction site between chromosome 8q and 3p was revealed in the samples CNE25, CNE29, and CNE211, which was the interaction between 1.5 kb downstream of ASAP1 and 0.8 kb upstream of CTNNB1 gene. Further quantitative polymerase chain reaction (qPCR) revealed that ASAP1 and CTNNB1 genes were more highly expressed in CNE25, CNE29, and CNE211 than in the Np group, preliminarily indicating that this interaction site was likely related to the high expression of ASAP1 and CTNNB1 in NPC.ConclusionsThrough Hi-C analysis, we analyzed the specific chromatin interaction sites associated with NPC, and found the chromosomal translocation and chromatin interaction sites associated with NPC based on statistical analysis. This study has certain guiding significance for in-depth study of the mechanism of NPC occurrence and development.

WNT8B as an Independent Prognostic Marker for Nasopharyngeal Carcinoma.

Background: Members of the Wnt signaling pathway have been shown to play a role in nasopharyngeal carcinoma (NPC) progression. Aim: The purpose of this study was to investigate WNT8B protein expression in NPC patients using tissue microarray (TMA) analysis and to evaluate its correlation with patient survival and clinical parameters. Methods: A total of 82 NPC cases, together with six normal nasopharyngeal tissue samples, were targeted to construct the TMA blocks. The WNT8B protein expression was evaluated by immunohistochemistry and its correlation to the clinicopathological features was investigated. Results: Sixty-two of 82 (75.6%) cases exhibited high WNT8B protein expression while 20/82 (24.4%) cases appeared to have low WNT8B expression. The univariate analysis revealed that systemic metastasis was associated with patient 5-year survival. The multivariate Cox proportional hazard regression analysis showed that WNT8B expression and systemic metastasis were significantly associated with the survival of NPC patients. Furthermore, there was no correlation found between the WNT8B protein expression and other clinicopathological parameters. Conclusion: Our results suggest that the expression of WNT8B is associated with NPC patients’ survival and could serve as an independent prognostic factor for NPC patients.