Therapeutic Target For Nasopharyngeal Carcinoma Research Articles

Tumor-derived exosomal miR-103a-3p promotes vascular permeability and proliferation by targeting ZO-1 and ACOX-1 in nasopharyngeal carcinoma.

miR-103a-3p has been reported to be a factor leading to poor prognosis in several human malignancies, including nasopharyngeal carcinoma (NPC). Secreted microRNAs containing exosomes may mediate the communication between cancer and stromal cells. The purpose of the current work was to learn more about miR-103a-3p's function in NPC exosomes. Transmission electron microscopy and NanoSight analysis were used to verify the existence of exosomes. To determine the relationship between exosomal miR-103a-3p and carcinogenesis in NPC, gain- and loss-of-function studies were carried out. Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, colony formation, flow cytometry, trans-endothelial invasion assays, endothelial permeability and cellular immunofluorescence were used to identify roles of exosomal miR-103a-3p in vitro. Zebrafish assay was used to disclose the effect of exosomal miR-103a-3p in vivo. Bioinformatics and dual-luciferase reporter assay were applied to clarify the mechanism of exosomal miR-103a-3p regulating the crosstalk between NPC cells and human umbilical vein endothelial cells (HUVECs). In the present study, we first demonstrated that the overexpression of exosomal miR-103a-3p improved NPC cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) progression in vitro. Then, we verified that NPC cell-derived exosomal miR-103a-3p destroyed the integrity of the endothelial monolayer in vitro and in vivo by downregulating zonula occludens 1 (ZO-1) expression. Moreover, we revealed that miR-103a-3p containing exosomes facilitated NPC cell proliferation through lipid droplet accumulation by direct target to metabolic enzyme acyl-CoA oxidase 1 (ACOX-1). Our data demonstrate that exosomal miR-103a-3p can facilitate the development of NPC by regulating the crosstalk between NPC cells and HUVECs. Exosomal miR-103a-3p could potentially serve as a therapeutic target for NPC.

The role and mechanism of circadian clock gene BMAL1 in the proliferation and metastasis of nasopharyngeal carcinoma by inhibition TGF-β1/Smads pathway.

6027 Background: To explore the molecular mechanism of biological clock gene BMAL1 inhibiting the proliferation and metastasis of nasopharyngeal carcinoma(NPC). Methods: 1. IHC detected the expression of BMAL1 in 41 cases of nasopharyngeal chronic inflammatory tissue and 71 cases of NPCtissue. PCR and Western blot measured the expression levels of BMAL1 in NP69 in NPC cells and human immortalized nasopharyngeal epithelial cells, respectively. 2. To detect the effect of BMAL1 on the proliferation capacity of NPCcells in vitro and in vivo; Scratch healing and Transwell invasion migration experiments detected the effect of BMAL1 on the invasion and migration ability of NPCcells in vitro. Fluorescence in vivo imaging and HE staining to determine the transfer of nude mouse tail intravenous injection model. PCR and Western blot detect the effect of BMAL1 on the expression of EMT-related markers at the transcriptional and protein levels in NPC cells. 3. A series of molecular biological means such as bioinformatics technology, ChIP experiment, double luciferase reporter gene experiment, immunofluorescence colocalization experiment and Co-IP were used to verify its mechanism. Results: 1. The expression of BMAL1 in NPCtissues and cells is reduced. The expression of BMAL1 in NPC tissues was associated with the M stage of nasopharyngeal carcinoma patients (p=0.006). 2. Overexpression of BMAL1 can inhibit the proliferation, invasion and migration ability of nasopharyngeal cancer cells, while knocking down BMAL1 is the opposite. Overexpression of BMAL1 inhibits EMT of NPCcells. 3. There are 5 BMAL1 binding sites in the TGF-β1promoter region, and BMAL1 can directly bind to the TGF-β1promoter region, which can inhibit the transcriptional activity of TGF-β1. Overexpression of BMAL1 inhibits TGF-β1/Smads pathway activity. Under the induction of recombinant human TGF-β1, the proliferation ability of NPC cells was enhanced, the activity of TGF-β1/Smads signaling pathway was enhanced, and nasopharyngeal cancer cells underwent EMT, and cell invasion and migration capacity increased. After overexpression of BMAL1, TGF-β1 no longer promotes TGF-β1/Smads signaling pathway activity, EMT is inhibited, and cell invasion and migration ability is weakened. BMAL1 combined with TGF-β1 has certain diagnostic value in predicting whether nasopharyngeal carcinoma metastasis. Conclusions: BMAL1 expression is downregulated in nasopharyngeal carcinoma, and its expression level is related to the development and metastasis of nasopharyngeal carcinoma. BMAL1 can inhibit the proliferation, epithelial-mesenchymal transformation and invasion and metastasis ability of NPC cells, and its mechanism is related to the inhibition of TGF-β1/Smads signaling pathway activity. It is speculated that it may become a new prognostic marker and therapeutic target for nasopharyngeal carcinoma.

Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma.

O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers.However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC.The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.

Integrating iron metabolism-related gene signature to evaluate prognosis and immune infiltration in nasopharyngeal carcinoma

BackgroundDysregulation of iron metabolism has been shown to have significant implications for cancer development. We aimed to investigate the prognostic and immunological significance of iron metabolism-related genes (IMRGs) in nasopharyngeal carcinoma (NPC).MethodsMultiple Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were analyzed to identify key IMRGs associated with prognosis. Additionally, the immunological significance of IMRGs was explored.ResultsA novel risk model was established using the LASSO regression algorithm, incorporating three genes (TFRC, SLC39A14, and ATP6V0D1).This model categorized patients into low and high-risk groups, and Kaplan–Meier analysis revealed significantly shorter progression-free survival for the high-risk group (P < 0.0001). The prognostic model’s accuracy was additionally confirmed by employing time-dependent Receiver Operating Characteristic (ROC) curves and conducting Decision Curve Analysis (DCA). High-risk patients were found to correlate with advanced clinical stages, specific tumor microenvironment subtypes, and distinct morphologies. ESTIMATE analysis demonstrated a significant inverse relationship between increased immune, stromal, and ESTIMATE scores and lowered risk score. Immune analysis indicated a negative correlation between high-risk score and the abundance of most tumor-infiltrating immune cells, including dendritic cells, CD8+ T cells, CD4+ T cells, and B cells. This correlation extended to immune checkpoint genes such as PDCD1, CTLA4, TIGIT, LAG3, and BTLA. The protein expression patterns of selected genes in clinical NPC samples were validated through immunohistochemistry.ConclusionThis study presents a prognostic model utilizing IMRGs in NPC, which could assist in assessing patient prognosis and provide insights into new therapeutic targets for NPC.

CPNE1, A Potential Therapeutic Target in Nasopharyngeal Carcinoma, Affects Cell Growth and Radiation Resistance.

The increased expression of Copine 1 (CPNE1) has been observed in various cancers, which promotes cell proliferation, apoptosis, and radio resistance. However, the potential mechanism of CPNE1 in nasopharyngeal carcinoma (NPC) remains elusive. Consequently, our objective was to investigate the role of CPNE1 in regulating proliferation and radio resistance of NPC. CPNE1 expression in NPC and normal patients were obtained from Cancer Genome Atlas (TCGA) database. An elevated CPNE1 was observed in NPC patients and cells (C666-1, SUNE-1, and HNE-1). Then, C666-1 and SUNE-1 cells were subjected to si-CPNE1 under different radiations (0-8 Gy). Cell growth and proliferation were measured by CCK8 and EDU assays, which demonstrated si-CPNE1 suppressed proliferation. Colony formation was performed to detect cell viability under different radiation therapy and survival curve of cell was plotted, which indicated that CPNE1 knockdown improved cell radiosensitivity. Additionally, flow cytometry showed silence of CPNE1 enhanced apoptosis rate in radiated cells. To further investigate the mechanisms of CPNE1 regulating NPC, the expression of activated phosphate Akt (p-Akt) was assessed through western blotting. We observed elevated p-Akt in si-CPNE1 transfected C666-1 and SUNE-1 cells. In conclusion, these results demonstrated that CPNE1 expression is elevated in nasopharyngeal carcinoma cells, and its silencing could attenuate nasopharyngeal carcinoma advancement and improve radiosensitivity to radiation therapy by controlling Akt activation.

Lactate dehydrogenase A promotes nasopharyngeal carcinoma progression through the TAK1/NF-κB Axis.

Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates in the nasopharyngeal mucosa and is common in China and Southeast Asian countries. Cancer cells reprogram glycolytic metabolism to promote their growth, survival and metastasis. Glycolysis plays an important role in NPC development, but the underlying mechanisms remain incompletely elucidated. Lactate dehydrogenase A (LDHA) is a crucial glycolytic enzyme, catalyzing the last step of glycolysis. This study aims to investigate the exact role of LDHA, which catalyzes the conversion of pyruvate into lactate, in NPC development. The western blot and immunohistochemical (IHC) results indicated that LDHA was significantly upregulated in NPC cells and clinical samples. LDHA knockdown by shRNA significantly inhibited NPC cell proliferation and invasion. Further knockdown of LDHA dramatically weakened the tumorigenicity of NPC cells in vivo. Mechanistic studies showed that LDHA activated TGF-β-activated kinase 1 (TAK1) and subsequent nuclear factor κB (NF-κB) signaling to promote NPC cell proliferation and invasion. Exogenous lactate supplementation restored NPC cell proliferation and invasion inhibited by LDHA knockdown, and this restorative effect was reversed by NF-κB inhibitor (BAY 11-7082) or TAK1 inhibitor (5Z-7-oxozeaenol) treatment. Moreover, clinical sample analyses showed that LDHA expression was positively correlated with TAK1 Thr187 phosphorylation and poor prognosis. Our results suggest that LDHA and its major metabolite lactate drive NPC progression by regulating TAK1 and its downstream NF-κB signaling, which could become a therapeutic target in NPC.

Elucidating the Immune Microenvironment and Therapeutic Targets in Nasopharyngeal Carcinoma through Bioinformatics

Elucidating the Immune Microenvironment and Therapeutic Targets in Nasopharyngeal Carcinoma through Bioinformatics

Knockdown of TFRC suppressed the progression of nasopharyngeal carcinoma by downregulating the PI3K/Akt/mTOR pathway

BackgroundThe transferrin receptor (TfR) encoded by TFRC gene is the main cellular iron importer. TfR is highly expressed in many cancers and is expected to be a promising new target for cancer therapy; however, its role in nasopharyngeal carcinoma (NPC) remains unknown.MethodsThe TfR levels were investigated in NPC tissues and cell lines using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. Knockdown of TFRC using two siRNA to investigate the effects on intracellular iron level and biological functions, including proliferation by CKK-8 assay, colony formation, cell apoptosis and cell cycle by flow cytometry, migration and invasion, and tumor growth in vivo by nude mouse xenografts. RNA sequencing was performed to find possible mechanism after TFRC knockdown on NPC cells and further verified by western blotting.ResultsTfR was overexpressed in NPC cell lines and tissues. Knockdown of TFRC inhibited cell proliferation concomitant with increased apoptosis and cell cycle arrest, and it decreased intracellular iron, colony formation, migration, invasion, and epithelial-mesenchymal transition in HK1-EBV cells. Western blotting showed that TFRC knockdown suppressed the levels of the iron storage protein FTH1, anti-apoptotic marker BCL-xL, and epithelial-mesenchymal transition markers. We confirmed in vivo that TFRC knockdown also inhibited NPC tumor growth and decreased Ki67 expression in tumor tissues of nude mouse xenografts. RNA sequencing and western blotting revealed that TFRC silencing inhibited the PI3K/Akt/mTOR signaling pathway.ConclusionsThese results indicated that TfR was overexpressed in NPC, and TFRC knockdown inhibited NPC progression by suppressing the PI3K/Akt/mTOR signaling pathway. Thus, TfR may serve as a novel biomarker and therapeutic target for NPC.

SRSF3/AMOTL1 splicing axis promotes the tumorigenesis of nasopharyngeal carcinoma through regulating the nucleus translocation of YAP1

Dysregulation of serine/arginine splicing factors (SRSFs) and abnormal alternative splicing (AS) have been widely implicated in various cancers but scarcely investigated in nasopharyngeal carcinoma (NPC). Here we examine the expression of 12 classical SRSFs between 87 NPC and 10 control samples, revealing a significant upregulation of SRSF3 and its association with worse prognosis in NPC. Functional assays demonstrate that SRSF3 exerts an oncogenic function in NPC progression. Transcriptome analysis reveals 1,934 SRSF3-regulated AS events in genes related to cell cycle and mRNA metabolism. Among these events, we verify the generation of a long isoform of AMOTL1 (AMOTL1-L) through a direct bond of the SRSF3 RRM domain with the exon 12 of AMOTL1 to promote exon inclusion. Functional studies also reveal that AMOTL1-L promotes the proliferation and migration of NPC cells, while AMOTL1-S does not. Furthermore, overexpression of AMOTL1-L, but not -S, significantly rescues the inhibitory effects of SRSF3 knockdown. Additionally, compared with AMOTL1-S, AMOTL1-L has a localization preference in the intracellular than the cell membrane, leading to a more robust interaction with YAP1 to promote nucleus translocation. Our findings identify SRSF3/AMOTL1 as a novel alternative splicing axis with pivotal roles in NPC development, which could serve as promising prognostic biomarkers and therapeutic targets for NPC.

Key Prediction Genes of Nasopharyngeal Carcinoma:Screening Based on Systematic Bioinformatics and Validation by Cell Experiments

Objective To screen out the potential prediction genes for nasopharyngeal carcinoma(NPC)from the gene microarray data of NPC samples and then verify the genes by cell experiments.Methods The NPC dataset was downloaded from Gene Expression Omnibus,and limma package was employed to screen out the differentially expressed genes.Weighted correlation network analysis package was used for weighted gene co-expression network analysis,and Venn diagram was drawn to find the common genes.The gene ontology annotation and Kyoto encyclopedia of genes and genomes pathway enrichment were then performed for the common genes.The biomarkers for NPC were further explored by protein-protein interaction network,LASSO regression,and non-parametric tests.Real-time quantitative PCR and Western blotting were employed to determine the mRNA and protein levels of key predictors of NPC,so as to verify the screening results.Results There were 622 up-regulated genes and 351 down-regulated genes in the GSE12452 dataset.A total of 116 common genes were obtained by limma analysis and weighted gene co-expression network analysis.The common genes were mainly involved in the biological processes of cell proliferation and regulation and regulation of intercellular adhesion.They were mainly enriched in Rap1,Ras,and tumor necrosis factor signaling pathways.Six key genes were screened out,encoding angiopoietin-2(ANGPT2),dual oxidase 2(DUOX2),coagulation factor Ⅲ(F3),interleukin-15(IL-15),lipocalin-2,and retinoic acid receptor-related orphan receptor B(RORB).Real-time quantitative PCR and Western blotting showed that the NPC cells had up-regulated mRNA and protein levels of ANGPT2 and IL-15 and down-regulated mRNA and protein levels of DUOX2,F3,and RORB,which was consistent with the results predicted by bioinformatics.Conclusion ANGPT2,DUOX2,F3,IL-15 and RORB are potential predictive molecular markers and therapeutic targets for NPC,which may be involved in Rap1,Ras,tumor necrosis factor and other signaling pathways.

Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis.

Nasopharyngeal carcinoma (NPC) is one of the most ordinary malignant tumors. Current research has suggested that circular RNAs play an important role in tumor genesis and progression. The purpose of this study is to explore the function and underlying mechanisms of circ_0028007 in NPC. The levels of circ_0028007, miR-1179, and Squalene epoxidase (SQLE) were detected by quantitative real-time polymerase chain reaction. Cell proliferation was detected by colony formation assay and thymidine analog 5-ethynyl-2'-deoxyuridine assay. Cell apoptosis was detected by flow cytometry. Relevant kits detected caspase-3, glucose, and lactate levels. Western blot assay was used to detect the related protein content. Dual-luciferase reporter assay and RNA pull-down assay were used to examine the target relationship between miR-1179 and circ_0028007 or SQLE. circ_0028007 and SQLE were highly expressed in NPC, while miR-1179 was lowly expressed. circ_0028007 silencing inhibited NPC cell proliferation and promoted apoptosis. However, the effect of circ_0028007 down-regulation on NPC cells was partially restored by co-transfection with miR-1179 inhibitor. Overexpression of SQLE partially restored the cell proliferation inhibited by circ_0028007 knockdown. circ_0028007 could regulate NPC progression via the miR-1179/SQLE axis. Therefore, circ_0028007 might be a new therapeutic target for NPC.

TOM40 regulates the progression of nasopharyngeal carcinoma through ROS-mediated AKT/mTOR and p53 signaling

Nasopharyngeal carcinoma (NPC) is a prevalent cancer in Southern China, North Africa, and Southeast Asia. The translocase of the outer membrane (TOM) 40 is a transporter of mitochondrial proteins, and is involved in ovarian cancer cell growth. However, its role in the progression of NPC is still unclear. We found that TOM40 levels were upregulated in NPC tissues and multiple NPC cell lines. In addition, high TOM40 expression in the tumor tissues was associated with poor overall survival and disease specific survival. TOM40 knockdown in the NPC cell lines inhibited their proliferation in vitro and in vivo. Furthermore, TOM40 silencing also increased intracellular production of reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP). Mechanistically, the anti-tumor effects of TOM40 silencing were dependent on the inhibition of AKT/mTOR signaling and activation of p53 signaling. To summarize, TOM40 mediates NPC progression through ROS-mediated AKT/mTOR and p53 signaling. Our findings highlight the potential of TOM40 as a therapeutic target for NPC.

Long noncoding RNA LINC00173 induces radioresistance in nasopharyngeal carcinoma via inhibiting CHK2/P53 pathway.

Radiotherapy is the backbone of nasopharyngeal carcinoma (NPC), nearly 11-17% NPC patients suffered local relapse and 18-37% suffered distant metastasis mainly due to radioresistance. Therefore, the key of improving patients' survivals is to investigate the mechanism of radioresistance. In this study, we revealed that the expression level of long intergenic nonprotein coding RNA 173 (LINC00173) was significantly increased in the radioresistant NPC patients' tumour tissues compared with the radiosensitive patients by RNA-sequencing, which also predict poor prognosis in NPC. Overexpression of LINC00173 induced radioresistance of NPC cells in vitro and in vivo. Mechanistically, LINC00173 bound with checkpoint kinase 2 (CHK2) in nucleus, and impaired the irradiation-induced CHK2 phosphorylation, then suppressed the activation of P53 signalling pathway, which eventually inhibiting apoptosis and leading to radioresistance in NPC cells. In summary, LINC00173 decreases the occurrence of apoptosis through inhibiting the CHK2/P53 pathway, leads to NPC radioresistance and could be considered as a novel predictor and therapeutic target in NPC.

LncRNA CASC19 Enhances the Radioresistance of Nasopharyngeal Carcinoma by Regulating the miR-340-3p/FKBP5 Axis.

Radioresistance remains a serious obstacle encountered in the radiotherapy of nasopharyngeal carcinoma (NPC). Both mRNAs and non-coding RNAs (ncRNAs), including long ncRNA (lncRNA) and microRNA (miRNA), play essential roles in radiosensitivity. However, the comprehensive expression profiles and competing endogenous RNA (ceRNA) regulatory networks among lncRNAs, miRNAs, and mRNAs in NPC radioresistance are still bewildering. In this study, we performed an RNA-sequencing (RNA-seq) assay in the radioresistant NPC cells CNE2R and its parental cells CNE2 to identify the differentially expressed lncRNAs, miRNAs, and mRNAs. The ceRNA networks containing lncRNAs, miRNAs, and mRNAs were predicted on the basis of the Pearson correlation coefficients and authoritative miRanda databases. In accordance with bioinformatic analysis of the data of the tandem mass tag (TMT) assay of CNE2R and CNE2 cells and the gene chip assay of radioresistant NPC samples in pre- and post-radiotherapy, the radioresistance-related signaling network of lncRNA CASC19, miR-340-3p, and FKBP5 was screened and further verified using an RT-qPCR assay. CASC19 was positively associated with FKBP5 expression while negatively correlated with miR-340-3p, and the target binding sites of CASC19/miR-340-3p and miR-340-3p/FKBP5 were confirmed using a dual-luciferase reporter assay. Moreover, using an mRFP-GFP-LC3 maker, it was found that autophagy contributed to the radioresistance of NPC. MiR-340-3p inhibition or FKBP5 overexpression could rescue the suppression of autophagy and radioresistance induced by CASC19 knockdown in CNE2R cells. In conclusion, the CASC19/miR-340-3p/FKBP5 network may be instrumental in regulating NPC radioresistance by enhancing autophagy, which provides potential new therapeutic targets for NPC.

Chemotherapy-Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA-Mediated PKR Activation.

Senescence is associated with tumor metastasis and chemotherapy resistance, yet the mechanisms remain elusive. Here, it is identified that nasopharyngeal carcinoma (NPC) patients who developed distant metastasis are characterized by senescence phenotypes, in which circWDR37 is a key regulator. CircWDR37 deficiency limits cisplatin or gemcitabine-induced senescent NPC cells from proliferation, migration, and invasion. Mechanistically, circWDR37 binds to and dimerizes double-stranded RNA-activated protein kinase R (PKR) to initiate PKR autophosphorylation and activation. Independent of its kinase activity, phosphorylated PKR induces I-kappaB kinase beta (IKKβ) phosphorylation, binds to and releases RELA from NF-κB inhibitor alpha (IκBα) to trigger nuclear factor kappa B (NF-κB) activation, thereby stimulating cyclin D1 (CCND1)and senescence-associated secretory phenotype component gene transcription in a circWDR37-dependent manner. Low circWDR37 levels correlate with chemotherapy response and favorable survival in NPC patients treated with gemcitabine or cisplatin induction chemotherapy. This study uncovers a new mechanism of circWDR37 activated PKR in senescence-driven metastasis and provides appealing therapeutic targets in NPC.

Upregulated Long Non-coding RNA Lnc-MRPL39-2:1 Induces the Growth and Invasion of Nasopharyngeal Carcinoma by Binding to HuR and Stabilizing β-Catenin mRNA.

Long non-coding RNAs (lncRNAs) have been to regulate tumor progression and therapy resistance through various molecular mechanisms. In this study, we investigated the role of lncRNAs in nasopharyngeal carcinoma (NPC) and the underlying mechanism. Using lncRNA arrays to analyze the lncRNA profiles of the NPC and para-tumor tissues, we detected the novel lnc-MRPL39-2:1, which was validated by in situ hybridization and by the 5' and 3' rapid amplification of the cDNA ends. Further, its role in NPC cell growth and metastasis was verified in vitro and in vivo. The researchers conducted the RNA pull-down assays, mass spectrometry (MS), dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and the MS2-RIP assays were then used to identify the lnc-MRPL39-2:1-interacting proteins and miRNAs. We found that lnc-MRPL39-2:1, which was highly expressed in in NPC tissues, was related to a poor prognosis in NPC patients. Furthermore, lnc-MRPL39-2:1 was shown to induce the growth and invasion of NPC by interacting directly with the Hu-antigen R (HuR) to upregulate β-catenin expression both in vivo and in vitro. Lnc-MRPL39-2:1 expression was also suppressed by microRNA (miR)-329. Thus, these findings indicate that lnc-MRPL39-2:1 is essential in NPC tumorigenesis and metastasis and highlight its potential as a prognostic marker and therapeutic target for NPC.

Transient receptor potential vanilloid type 4 (TRPV4) promotes tumorigenesis via NFAT4 activation in nasopharyngeal carcinoma.

Transient receptor potential vanilloid type 4 (TRPV4) can function as an oncogene or tumor suppressor depending on the tumor types. However, little is known regarding the effect of TRPV4 in nasopharyngeal carcinoma (NPC), a highly prevalent malignancy in Southern China and Southeast Asia. We found that TRPV4 mRNA and protein levels were significantly upregulated in NPC tissues. In addition, activation of TRPV4 in NPC cell lines using GSK1016790A (100nM) induced a Ca2+ influx, whereas pharmacological inhibition or gene knockdown of TRPV4 reduced the proliferation rates of NPC cells. TRPV4 knockdown also decreased the growth of tumor xenografts in vivo. Mechanistically, TRPV4-mediated tumorigenesis is dependent on the activation of Ca2+/calcineurin/calcineurin-nuclear factor of activated T cell 4 (NFAT4) signaling. Furthermore, NFAT4 protein level was overexpressed in NPC tissues and correlated positively with TRPV4. Taken together, TRPV4 promotes the malignant potential of NPC cells by activating NFAT4 signaling. Our findings highlight TRPV4-NFAT4 axis as a potential therapeutic target in NPC.

Screening Key Genes and Biological Pathways in Nasopharyngeal Carcinoma by Integrated Bioinformatics Analysis.

The purpose of this study was to identify the hub genes and biological pathways of nasopharyngeal carcinoma (NPC) through bioinformatics analysis and potential new therapeutic targets. In this study, three datasets were downloaded from the Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) between NPC and normal tissues were analyzed using the GEO2R online tool. Volcano and heat maps of the DEGs were visualized using the hiplot database. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the upregulated and downregulated DEGs were performed using the DAVID database. Finally, we established a protein-protein interaction (PPI) network using the STRING database and showed the differential expression of hub genes between the normal and tumor tissues. In all, 109,371,221 upregulated DEGs and 139,226,520 downregulated DEGs were obtained in datasets GSE40290, GSE61218, and GSE53819, respectively, and 18 common differential genes, named co-DEGs, were screened in the three datasets. The most abundant biological GO terms of the co-DEGs were inflammatory response et al. The KEGG pathway enrichment analysis showed that co-DEGs mainly participated in the interleukin (IL)-17 signaling pathway et al. Finally, we identified four hub genes using PPI analysis and observed that three of them were highly expressed in tumor tissues. In this study, the hub genes of NPC, such as PTGS2, and pathways such as IL-17 signaling, were identified through bioinformatics analysis, which may be potential new therapeutic targets for NPC.

N6 -Methyladenosine-Modified CBX1 Regulates Nasopharyngeal Carcinoma Progression Through Heterochromatin Formation and STAT1 Activation.

Epitranscriptomic remodeling such as N6 -methyladenosine (m6 A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m6 A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m6 A hypomethylation in metastatic NPC tissues. The m6 A-modified CBX1 mRNA transcript is recognized and destabilized by the m6 A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.

Upregulation of ITGAV and the underlying mechanisms in nasopharyngeal carcinoma

BackgroundIntegrin subunit α -v (ITGAV) has been demonstrated to be dysregulated and involved in cancer promotion processes in a variety of cancers, but studies on nasopharyngeal carcinoma (NPC) have been limited. Our study aimed to comprehensively assess the expression level and potential mechanisms of ITGAV in NPC. ResultsA total of 13 mRNA expression datasets and internal tissue microarrays were included. ITGAV protein and mRNA were overexpressed in NPC. The pathways of upregulated genes positively related to ITGAV in NPC were analyzed, and the PI3K−Akt signaling pathway, cell cycle, and human papillomavirus infections were most significantly enriched. The protein–protein interaction network was constructed for the genes enriched in these pathways, and the corresponding hub genes were obtained. Among them, breast cancer susceptibility gene 1 (BRCA1) was predicted to be a transcription factor of ITGAV via the Cistrome DB Toolkit, which was also confirmed by ChIP-seq information and correlation calculations. ConclusionsITGAV is overexpressed in NPC and can regulate BRCA1 to participate in the cancer process. ITGAV serves as a potential therapeutic target in NPC patients.How to cite: Huang S-W, Luo J-Y, Qin L-T, et al. Upregulation of ITGAV and the underlying mechanisms in nasopharyngeal carcinoma. Electron J Biotechnol 2022;60. https://doi.org/10.1016/j.ejbt.2022.09.002.