Association of Matrix Metalloproteinase-9 Genotypes With Nasopharyngeal Carcinoma Risk.

BACKGROUND/AIM: The up-regulation of matrix metalloproteinase-9 (MMP-9) expression is a characteristic feature observed across various malignancies, including nasopharyngeal carcinoma (NPC). Nevertheless, the influence of MMP-9 genotype in the context of NPC remains underexplored. This study examined the implications of MMP-9 promoter rs3918242 genotypes on the susceptibility to NPC in Taiwan. MATERIALS AND METHODS: In a cohort comprising 208 NPC cases and 416 healthy controls, genotyping of MMP-9 rs3918242 was conducted utilizing polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: Individuals harbouring the variant CT or TT genotype of MMP-9 rs3918242 did not demonstrate a discernible alteration in NPC risk when compared to wild-type CC carriers [odds ratio (OR)=0.83 and 0.79, with 95% confidence intervals (95%CI)=0.56-1.24 and 0.27-2.29; p=0.4205 and 0.8675, respectively]. Moreover, the presence of the variant T allele did not confer a modified risk of NPC (OR=0.84, 95%CI=0.60-1.19, p=0.3761). Intriguingly, a protective effect associated with the MMP-9 rs3918242 CT genotype against NPC risk was discerned among individuals abstaining from betel quid chewing behaviour (OR=0.51, 95%CI=0.30-0.87, p=0.0166). Notably, no significant association was established between the MMP-9 rs3918242 CT or TT genotype and NPC risk among individuals with or without smoking or alcohol consumption habits. CONCLUSION: Presence of the variant CT or TT genotype at MMP-9 rs3918242 did not appear to substantially contribute to an elevated risk of NPC. Notably, a protective effect against NPC risk was observed in individuals carrying the CT genotype, particularly in those abstaining from betel quid chewing.

Tumor-associated characteristics and immune dysregulation in nasopharyngeal carcinoma under the regulation of m7G-related tumor microenvironment cells.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a type of malignant tumor with high morbidity. Aberrant levels of N7-methylguanosine (m7G) are closely associated with tumor progression. However, the characteristics of the tumor microenvironment (TME) in NPC associated with m7G modification remain unclear. METHODS: A total of 68,795 single cells from single-cell RNA sequencing data derived from 11 NPC tumor samples and 3 nasopharyngeal lymphatic hyperplasia (NLH) samples were clustered using a nonnegative matrix factorization algorithm according to 61 m7G RNA modification regulators. RESULTS: The m7G regulators were found differential expression in the TME cells of NPC, and most m7G-related immune cell clusters in NPC tissues had a higher abundance compared to non-NPC tissues. Specifically, m7G scores in the CD4+ and CD8+ T cell clusters were significantly lower in NPC than in NLH. T cell clusters differentially expressed immune co-stimulators and co-inhibitors. Macrophage clusters differentially expressed EIF4A1, and high EIF4A1 expression was associated with poor survival in patients with head and neck squamous carcinoma. EIF4A1 was upregulated in NPC tissues compared to the non-NPC tissues and mainly expressed in CD86+ macrophages. Moreover, B cell clusters exhibited tumor biological characteristics under the regulation of m7G-related genes in NPC. The fibroblast clusters interacted with the above immune cell clusters and enriched tumor biological pathways, such as FGER2 signaling pathway. Importantly, there were correlations and interactions through various ligand-receptor links among epithelial cells and m7G-related TME cell clusters. CONCLUSION: Our study revealed tumor-associated characteristics and immune dysregulation in the NPC microenvironment under the regulation of m7G-related TME cells. These results demonstrated the underlying regulatory roles of m7G in NPC.

Exosome-Mediated Transfer of ALDH2 in Nasopharyngeal Carcinoma Cells Confers Increased Resistance to Paclitaxel Treatment.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an aggressive and highly metastatic malignant tumor. Despite recent therapeutic advances, resistance to Taxol (the generic name of paclitaxel) therapy remains a major challenge in clinical management. Therefore, it is imperative to explore the potential mechanisms of paclitaxel resistance in NPC. This study aimed to investigate the expression of aldehyde dehydrogenase 2 (ALDH2) in NPC cells and its critical role in paclitaxel resistance. METHODS: Paclitaxel-resistant cell line CNE1/Taxol (CNE1-TR), a drug-resistant cell line, was established by exposing the CNE1 nasopharyngeal carcinoma cell line to progressively increasing concentrations of paclitaxel. Furthermore, we investigated the role of ALDH2 in paclitaxel resistance and the function of exosomes using cell culture, Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), Cell Counting Kit-8 (CCK-8), and nanoparticle tracking analysis. RESULTS: The results showed that in the presence of paclitaxel, the CNE1-TR cells manifested higher survival rate and half-maximal inhibitory concentration (IC50) value compared to the parental cell line, indicating strong resistance to paclitaxel. CNE1-TR cells had significantly upregulated mRNA and protein levels of ALDH2. In addition, exosome analysis showed that CNE1-TR cells were able to deliver ALDH2 via exosomes, increasing paclitaxel resistance in the recipient cells. We observed that the ALDH2 expression levels and paclitaxel resistance in CNE1-TR cells were effectively reduced by blocking the release of exosomes. CONCLUSION: ALDH2 is not only a key molecular marker indicative of therapeutic efficacy, but also a potential therapeutic target for developing novel anticancer strategies. By blocking the exosomal transport of ALDH2 or directly inhibiting its activity, it may be possible to overcome paclitaxel resistance, thus improving the success rate of clinical treatment.

Expression and functional implications of YME1L in nasopharyngeal carcinoma.

Mitochondria play a crucial role in the progression of nasopharyngeal carcinoma (NPC). YME1L, a member of the AAA ATPase family, is a key regulator of mitochondrial function and has been implicated in various cellular processes and diseases. This study investigates the expression and functional significance of YME1L in NPC. YME1L exhibits significant upregulation in NPC tissues from patients and across various primary human NPC cells, while its expression remains relatively low in adjacent normal tissues and primary nasal epithelial cells. Employing genetic silencing through the shRNA strategy or knockout (KO) via the CRISPR-sgRNA method, we demonstrated that YME1L depletion disrupted mitochondrial function, leading to mitochondrial depolarization, reactive oxygen species (ROS) generation, lipid peroxidation, and ATP reduction within primary NPC cells. Additionally, YME1L silencing or KO substantially impeded cell viability, proliferation, cell cycle progression, and migratory capabilities, concomitant with an augmentation of Caspase-apoptosis activation in primary NPC cells. Conversely, ectopic YME1L expression conferred pro-tumorigenic attributes, enhancing ATP production and bolstering NPC cell proliferation and migration. Moreover, our findings illuminate the pivotal role of YME1L in Akt-mTOR activation within NPC cells, with Akt-S6K phosphorylation exhibiting a significant decline upon YME1L depletion but enhancement upon YME1L overexpression. In YME1L-silenced primary NPC cells, the introduction of a constitutively-active Akt1 mutant (caAkt1, at S473D) restored Akt-S6K phosphorylation, effectively ameliorating the inhibitory effects imposed by YME1L shRNA. In vivo studies revealed that intratumoral administration of YME1L-shRNA-expressing adeno-associated virus (AAV) curtailed subcutaneous NPC xenograft growth in nude mice. Furthermore, YME1L downregulation, concurrent with mitochondrial dysfunction and ATP reduction, oxidative injury, Akt-mTOR inactivation, and apoptosis induction were evident within YME1L-silenced NPC xenograft tissues. Collectively, these findings shed light on the notable pro-tumorigenic role by overexpressed YME1L in NPC, with a plausible mechanism involving the promotion of Akt-mTOR activation.

PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma.

Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.

The Relationship Between the hOGG1 rs1052133 Polymorphism and the Occurrence of Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis.

Objectives: Exploring the relationship between the hOGG1 rs1052133 polymorphism and the occurrence of nasopharyngeal carcinoma (NPC). Methods: PubMed, Web of Science, Scopus, CNKI, Wanfangdata, and VIP were used to search for studies and the NOS evaluation scale was used to evaluate the quality. All studies were grouped according to different genotypes. The Cochrane's Q test and I2 test were used for heterogeneity evaluations. If heterogeneity was small, the fixed effects model was used, and conversely, the random effects model was used. Publication bias was also detected. P < .05 in all results indicated statistically significant. Results: We ultimately included 6 studies with 2021 NPC patients in the study group and 2375 healthy populations in the control group. After meta-analysis, it was found that the total OR value of the "Ser/Cys (CG) vs Ser/Ser (CC)" group was 1.00 (95% CI: 0.85-1.18) and the "Cys/Cys (GG) vs Ser/Ser (CC)" group was 1.06 (95% CI: 0.87-1.28). These results were not statistically significant (P > .05). Furthermore, the integrated total OR values of each group were not statistically significant with or without the smoking history, even in other genotype models (Allele, Dominant, Recessive, and Additive) (P > .05). Conclusion: There is no clear correlation between the hOGG1 rs1052133 polymorphism and the occurrence of NPC, even with or without the smoking history.

Meta-analysis of Epstein-Barr virus genomes in Southern Chinese identifies genetic variants and high risk viral lineage associated with nasopharyngeal carcinoma.

Genetic variants in Epstein-Barr virus (EBV) have been strongly associated with nasopharyngeal carcinoma (NPC) in South China. However, different results regarding the most significant viral variants, with polymorphisms in EBER2 and BALF2 loci, have been reported in separate studies. In this study, we newly sequenced 100 EBV genomes derived from 61 NPC cases and 39 population controls. Comprehensive genomic analyses of EBV sequences from both NPC patients and healthy carriers in South China were conducted, totaling 279 cases and 227 controls. Meta-analysis of genome-wide association study revealed a 4-bp deletion downstream of EBER2 (coordinates, 7188-7191; EBER-del) as the most significant variant associated with NPC. Furthermore, multiple viral variants were found to be genetically linked to EBER-del forming a risk haplotype, suggesting that multiple viral variants might be associated with NPC pathogenesis. Population structure and phylogenetic analyses further characterized a high risk EBV lineage for NPC revealing a panel of 38 single nucleotide polymorphisms (SNPs), including those in the EBER2 and BALF2 loci. With linkage disequilibrium clumping and feature selection algorithm, the 38 SNPs could be narrowed down to 9 SNPs which can be used to accurately detect the high risk EBV lineage. In summary, our study provides novel insight into the role of EBV genetic variation in NPC pathogenesis by defining a risk haplotype of EBV for downstream functional studies and identifying a single high risk EBV lineage characterized by 9 SNPs for potential application in population screening of NPC.

FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.

Chitinase 3 like-1 activates the Akt pathway, inducing NF-κB-dependent release of pro-inflammatory cytokines and promoting the proliferative ability in nasopharyngeal carcinoma cells.

BACKGROUND: Chitinase 3 like-1 (CHI3L1) has been reported to function as an oncogene in many types of cancer. However, the biological function of CHI3L1 in nasopharyngeal carcinoma (NPC) remains unknown. METHODS: Differentially expressed genes (DEGs) in NPC tissues in GSE64634 and GSE12452 were downloaded from Gene Expression Omnibus (GEO). CHI3L1, interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) mRNA expression was examined by qRT-PCR. Cell proliferation was evaluated by CCK-8 and EdU incorporation assays. Western blot analysis was used to measure the changes of CHI3L1, nuclear factor-κappaB (NF-κB), and protein kinase B (Akt) pathways. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses were performed using DAVID database. RESULTS: We identified 3 overlapping DEGs using Draw Venn diagram, among which CHI3L1 was chosen for the following analyses. CHI3L1 was upregulated in NPC tissues and cells. CHI3L1 silencing suppressed inflammatory response by inactivating the NF-κB pathway and inhibited cell proliferation in NPC cells. On the contrary, CHI3L1 overexpression induced inflammatory response by activating the NF-κB pathway and promoted cell proliferation in NPC cells. According to GO and KEGG analyses, CHI3L1 positive regulates Akt signaling and is enriched in the PI3K-Akt pathway. CHI3L1 knockdown inhibited the Akt pathway, and CHI3L1 overexpression activated the Akt pathway in NPC cells. Akt overexpression abolished the effects of CHI3L1 knockdown on inflammatory response, NF-κB pathway, and proliferation in NPC cells. On the contrary, Akt knockdown abolished the effects of CHI3L1 overexpression on inflammatory response, NF-κB pathway, and proliferation in NPC cells. CONCLUSION: CHI3L1 knockdown inhibited NF-κB-dependent inflammatory response and promoting proliferation in NPC cells by inactivating the Akt pathway.

The Role of PTEN in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck tumor that is influenced by a variety of molecular factors during its pathogenesis. Among these, the phosphatase and tensin homolog (PTEN) plays a crucial role in regulatory networks. This article systematically reviews the multifaceted functions of PTEN in NPC, including its roles in inhibiting cell proliferation, regulating migration and invasion, promoting autophagy and apoptosis, and influencing resistance to radiotherapy. Molecular factors such as long non-coding RNA, microRNA (miRNA), and circular RNA can modulate PTEN through various pathways, thereby impacting the biological behavior of NPC. In addition, PTEN is involved in regulating the tumor microenvironment of NPC, and its interaction with the Epstein-Barr virus has also recently become a focus of research. A comprehensive understanding of the PTEN regulatory network provides a foundation for future personalized and targeted therapeutic strategies. This study expands our understanding of the pathogenesis of NPC and suggests new directions in the field of tumor biology and NPC treatment.

Comprehensive analysis of recently discovered lncRNA-associated competing endogenous RNA network in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharynx and is characterized by geography-dependent incidence. Despite the high mortality rate, specifically in some ethnic groups, the mechanisms underlying NPC pathogenesis are not thoroughly understood and there is an urgent need to detect the potential and clinically applicable biomarkers to ameliorate the overall survival rate and improve the prognosis of patients. In recent years, research has increasingly focused on the importance of long non-coding RNAs (LncRNAs) in cancer progression. LncRNAs play critical roles in regulating gene expression through mechanisms such as competitively binding to microRNAs (CeRNA). While numerous LncRNAs have been studied in nasopharyngeal carcinoma (NPC), their potential as diagnostic and prognostic biomarkers have not been systematically examined. In the present study, we delve into elucidating the biological functions, molecular mechanisms, and clinical significance of newly identified LncRNAs that serve as sponges for different microRNAs in NPC. We highlight their regulatory mechanisms in promoting cell proliferation, invasion, and metastasis, and discuss their implications in diverse cancer-related signaling pathways. Our overall goal is to emboss the fundamental roles of LncRNA-mediated CeRNA networks in NPC progression, which may open up new avenues for determining the pathogenesis of NPC and developing effective prevention and treatment strategies.

Explore the shared molecular mechanism between dermatomyositis and nasopharyngeal cancer by bioinformatic analysis.

BACKGROUND: Dermatomyositis (DM) is prone to nasopharyngeal carcinoma (NPC), but the mechanism is unclear. This study aimed to explore the potential pathogenesis of DM and NPC. METHODS: The datasets GSE46239, GSE142807, GSE12452, and GSE53819 were downloaded from the GEO dataset. The disease co-expression module was obtained by R-package WGCNA. We built PPI networks for the key modules. ClueGO was used to analyze functional enrichment for the key modules. DEG analysis was performed with the R-package "limma". R-package "pROC" was applied to assess the diagnostic performance of hub genes. MiRNA-mRNA networks were constructed using MiRTarBase and miRWalk databases. RESULTS: The key modules that positively correlated with NPC and DM were found. Its intersecting genes were enriched in the negative regulation of viral gene replication pathway. Similarly, overlapping down-regulated DEGs in DM and NPC were also enriched in negatively regulated viral gene replication. Finally, we identified 10 hub genes that primarily regulate viral biological processes and type I interferon responses. Four key genes (GBP1, IFIH1, IFIT3, BST2) showed strong diagnostic performance, with AUC>0.8. In both DM and NPC, the expression of key genes was correlated with macrophage infiltration level. Based on hub genes' miRNA-mRNA network, hsa-miR-146a plays a vital role in DM-associated NPC. CONCLUSIONS: Our research discovered pivot genes between DM and NPC. Viral gene replication and response to type I interferon may be the crucial bridge between DM and NPC. By regulating hub genes, MiR-146a will provide new strategies for diagnosis and treatment in DM complicated by NPC patients. For individuals with persistent viral replication in DM, screening for nasopharyngeal cancer is necessary.

MiR-122-5p regulates erastin-induced ferroptosis via CS in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a tumor that occurs in the nasopharynx. Although advances in detection and treatment have improved the prognosis of NPC the treatment of advanced NPC remains challenging. Here, we explored the effect of microRNA (miR)-122-5p on erastin-induced ferroptosis in NPC cells and the role of ferroptosis in the development of NPC. The effect of miR-122-5p silencing and overexpression and the effect of citrate synthase on erastin-induced lipid peroxidation in NPC cells was analyzed by measuring the amounts of malondialdehyde, Fe2+, glutathione, and reactive oxygen species and the morphological alterations of mitochondria. The malignant biological behavior of NPC cells was examined by cell counting kit-8, EDU, colony formation, Transwell, and wound healing assays. The effects of miR-122-5p on cell proliferation and migration associated with ferroptosis were examined in vivo in a mouse model of NPC generated by subcutaneous injection of NPC cells. We found that erastin induced ferroptosis in NPC cells. miR-122-5p overexpression inhibited CS, thereby promoting erastin-induced ferroptosis in NPC cells and decreasing NPC cell proliferation, migration, and invasion.

Using the genomic adjusted radiation dose (GARD) to personalize the radiation dose in nasopharyngeal cancer.

BACKGROUND: Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control. METHODS: A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR). RESULTS: Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66-76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1-67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66-74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %). CONCLUSION: GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.

KLF5 regulates actin remodeling to enhance the metastasis of nasopharyngeal carcinoma.

Transcription factors (TFs) engage in various cellular essential processes including differentiation, growth and migration. However, the master TF involved in distant metastasis of nasopharyngeal carcinoma (NPC) remains largely unclear. Here we show that KLF5 regulates actin remodeling to enhance NPC metastasis. We analyzed the msVIPER algorithm-generated transcriptional regulatory networks and identified KLF5 as a master TF of metastatic NPC linked to poor clinical outcomes. KLF5 regulates actin remodeling and lamellipodia formation to promote the metastasis of NPC cells in vitro and in vivo. Mechanistically, KLF5 preferentially occupies distal enhancer regions of ACTN4 to activate its transcription, whereby decoding the informative DNA sequences. ACTN4, extensively localized within actin cytoskeleton, facilitates dense and branched actin networks and lamellipodia formation at the cell leading edge, empowering cells to migrate faster. Collectively, our findings reveal that KLF5 controls robust transcription program of ACTN4 to modulate actin remodeling and augment cell motility which enhances NPC metastasis, and provide new potential biomarkers and therapeutic interventions for NPC.

LINC00313 suppresses autophagy and promotes stemness of nasopharyngeal carcinoma cells through PTBP1/STIM1 axis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a kind of malignant head and neck tumor with high mortality. lncRNAs are valuable diagnostic biomarkers and therapeutic targets for various tumors. This study investigated the effects and mechanism of LINC00313 in nasopharyngeal carcinoma. METHODS: Cell Counting Kit-8 (CCK-8) and immunohistochemistry were used for assessing cell proliferation. The levels of autophagy-related proteins, and stem cell markers were detected. Immunofluorescence assay was used for LC3 detection. Methylated RNA Immunoprecipitation (meRIP) of LINC00313 in NPC cells was assessed. The localization of LINC00313 was verified by luorescence in situ hybridization (FIHS). The interaction between LINC00313 and the downstream targets were analyzed and confirmed by immunoprecipitation (RIP). Besides, the tumorigenesis roles of LINC00313 were confirmed in tumor growth mice model. RESULTS: LINC00313 was increased in NPC tissues and cells. LINC00313 knockdown enhanced autophagy, and decreased stemness and cell viability of NPC cells through regulating STIM1. METTL3/IGF2BP1-mediated m6A modification promoted the stabilization and up-regulation of LINC00313. LINC00313 activated AKT/mTOR pathway in NPC cells through PTBP1/STIM1 axis. Moreover, LINC00313 promoted tumor growth and metastasis in xenograft model. CONCLUSION: Upregulation of LINC00313 suppressed autophagy and promoted stemness of NPC cells through PTBP1/STIM1 axis.

Homeobox B2 promotes malignant behavior and contributes to the radioresistance of nasopharyngeal carcinoma by regulating forkhead box protein O1.

Background: Nasopharyngeal carcinoma (NPC) is an epithelial tumor of the head and neck with heterogeneous racial and geographical distributions. Homeobox B2 (HOXB2) is a tumor promoter in many cancers. However, the biological role of HOXB2 in NPC has not been elucidated. Methods: Bioinformatics analysis was performed to identify the differentially expressed genes (DEGs) between samples of patients with radiosensitive and radioresistant NPC. qRT-PCR, western blotting and immunohistochemistry were used to detect the expression levels of the corresponding mRNA and proteins. Cell viability was detected by CCK-8 assay and colony-forming capability was evaluated using colony formation assays. Further, migration and invasion abilities were examined using wound-healing and transwell chamber assays, respectively. Cellular apoptosis after irradiation was assessed using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Results: HOXB2 was identified as a potential regulator of radioresistance in NPC. Our in vitro results indicate that HOXB2 overexpression (HOXB2-OE) promoted malignant behaviors including invasion, migration, proliferation, and inhibited the irradiation-induced apoptosis of NPC cells. Consistent with these results, HOXB2 knockdown (HOXB2-sh) exhibited the opposite trends in these biological activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs were enriched in the FOXO signaling pathway. Mechanistically, western blotting showed that HOXB2-OE inhibited forkhead box protein O1 (FOXO1) expression in NPC cells. Thereafter, we transferred the FOXO1-OE plasmid to HOXB2-OE NPC cells and found that overexpression of FOXO1 reversed cell proliferation, migration, invasion, and radioresistance profiles promoted by HOXB2 overexpression. Conclusion: Our findings showed that HOXB2 acts as a tumor promoter in NPC, activating malignant behaviors and radioresistance of tumors via FOXO1 regulation. Moreover, the inactivation of HOXB2 or activation of FOXO1 are potential strategies to inhibit tumor progression and overcome radioresistance in NPC.

Synergistic action of Hedyotis diffusa Willd and Andrographis paniculata in Nasopharyngeal Carcinoma: Downregulating AKT1 and upregulating VEGFA to curb tumorigenesis.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) remains a challenging cancer to treat. This study investigates the molecular mechanisms of Hedyotis diffusa Willd (HDW) combined with Andrographis paniculata (AP) in treating NPC. METHODS: Key compounds and target genes in HDW and AP were analyzed using network pharmacology. Protein-protein interaction (PPI) networks were constructed with STRING and visualized using Cytoscape. MCODE identified critical clusters, while DAVID facilitated GO and KEGG analyses. In vivo and in vitro experiments evaluated HDW-AP effects on NPC, including tumor volume, weight, Ki-67 expression, cell apoptosis, migration, invasion, cell cycle distribution, and DNA damage. RESULTS: The database identified 495 NPC-related genes and 26 compounds in the HDW-AP pair, targeting 165 genes. Fifty-eight potential therapeutic genes were found, leading to 18 key targets. KEGG analysis revealed a significant impact on 78 pathways, especially cancer pathways. Both in vivo and in vitro tests showed HDW-AP inhibited NPC cell proliferation, migration, invasion, and induced apoptosis. Mechanistically, this was achieved through AKT1 downregulation and VEGFA upregulation. CONCLUSION: The combination of HDW and AP targets 16 key genes to impede the development of NPC, primarily by modulating AKT1 and VEGFA pathways.