-
Cell Death & Disease Jul 2023Oncogenic super-enhancers (SEs) generate noncoding enhancer/SE RNAs (eRNAs/seRNAs) that exert a critical function in malignancy through powerful regulation of target...
Oncogenic super-enhancers (SEs) generate noncoding enhancer/SE RNAs (eRNAs/seRNAs) that exert a critical function in malignancy through powerful regulation of target gene expression. Herein, we show that a JUN-mediated seRNA can form R-loop to regulate target genes to promote metastasis of nasopharyngeal carcinoma (NPC). A combination of global run-on sequencing, chromatin-immunoprecipitation sequencing, and RNA sequencing was used to screen seRNAs. A specific seRNA associated with NPC metastasis (seRNA-NPCM) was identified as a transcriptional regulator for N-myc downstream-regulated gene 1 (NDRG1). JUN was found to regulate seRNA-NPCM through motif binding. seRNA-NPCM was elevated in NPC cancer tissues and highly metastatic cell lines, and promoted the metastasis of NPC cells in vitro and in vivo. Mechanistically, the 3' end of seRNA-NPCM hybridizes with the SE region to form an R-loop, and the middle segment of seRNA-NPCM binds to heterogeneous nuclear ribonucleoprotein R (hnRNPR) at the promoter of distal gene NDRG1 and neighboring gene tribbles pseudokinase 1 (TRIB1). These structures promote chromatin looping and long-distance chromatin interactions between SEs and promoters, thus facilitating NDRG1 and TRIB1 transcription. Furthermore, the clinical analyses showed that seRNA-NPCM and NDRG1 were independent prognostic factors for NPC patients. seRNA-NPCM plays a critical role in orchestrating target gene transcription to promote NPC metastasis.
Topics: Humans; Nasopharyngeal Carcinoma; RNA; R-Loop Structures; Carcinoma; Chromatin; Nasopharyngeal Neoplasms; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins
PubMed: 37479693
DOI: 10.1038/s41419-023-05985-9 -
Current Opinion in Immunology Aug 2023Epstein-Barr virus (EBV) contributes to oncogenesis and immune evasion in nasopharyngeal carcinoma (NPC). At present, an aggregated, higher-level view on the impact of... (Review)
Review
Epstein-Barr virus (EBV) contributes to oncogenesis and immune evasion in nasopharyngeal carcinoma (NPC). At present, an aggregated, higher-level view on the impact of EBV genes toward the immune microenvironment of NPC is lacking. To this end, we have interrogated tumor-derived RNA sequences of 106 treatment-naive NPC patients for 98 EBV transcripts, and captured the presence of 10 different immune cell populations as well as 23 different modes of T-cell evasion. We discovered 3 clusters of EBV genes that each associate with distinct immunophenotypes of NPC. Cluster 1 associated with gene sets related to immune cell recruitment, such as those encoding for chemoattractants and their receptors. Cluster 2 associated with antigen processing and presentation, such as interferon-related genes, whereas cluster 3 associated with presence of M1-like macrophages, absence of CD4+ T cells, and oncogenic pathways, such as the nuclear factor kappa light-chain enhancer of activated B-cell pathway. We discuss these 3 EBV clusters regarding their potential for stratification for T-cell immunity in NPC together with the next steps needed to validate such therapeutic value.
Topics: Humans; Nasopharyngeal Carcinoma; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Carcinoma; Nasopharyngeal Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 37235920
DOI: 10.1016/j.coi.2023.102335 -
Cancer Cell Mar 2024The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed...
The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.
Topics: Humans; Nasopharyngeal Carcinoma; Neoplasm Staging; Herpesvirus 4, Human; Prognosis; Nasopharyngeal Neoplasms; Epstein-Barr Virus Infections; Carcinoma; Retrospective Studies
PubMed: 38242125
DOI: 10.1016/j.ccell.2023.12.020 -
Oncogene Sep 2023The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most... (Review)
Review
The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most common HPV-induced cancer in developed countries. Since patients with HPV + OPSCC respond very favorably to standard aggressive treatment, the emphasis has changed to reducing treatment intensity. However, recent multi-center clinical trials failed to show non-inferiority of de-escalation strategies on a population basis, highlighting the need to select low-risk patients likely to respond to de-intensified treatments. In contrast, there is a substantial proportion of patients who develop recurrent disease despite aggressive therapy. This supports that HPV + OPSCC is not a homogeneous disease, but comprises distinct subtypes with clinical and biological variations. The overall goal for this review is to identify biomarkers for HPV + OPSCC that may be relevant for patient stratification for personalized treatment. We discuss HPV + OPSCC as a heterogeneous disease from multifaceted perspectives including clinical behavior, tumor morphology, and molecular phenotype. Molecular profiling from bulk tumors as well as single-cell sequencing data are discussed as potential driving factors of heterogeneity between tumor subgroups. Finally, we evaluate key challenges that may impede in-depth investigations of HPV + OPSCC heterogeneity and outline potential future directions, including a section on racial and ethnic differences.
Topics: Humans; Carcinoma, Squamous Cell; Papillomavirus Infections; Oropharyngeal Neoplasms; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Papillomaviridae
PubMed: 37666939
DOI: 10.1038/s41388-023-02819-y -
EBioMedicine Oct 2023Dysbiosis of the oral mycobiome has been linked to some diseases, including cancers. However, the role of oral fungal communities in nasopharyngeal carcinoma (NPC)...
BACKGROUND
Dysbiosis of the oral mycobiome has been linked to some diseases, including cancers. However, the role of oral fungal communities in nasopharyngeal carcinoma (NPC) carcinogenesis has not previously been investigated.
METHODS
We characterized the oral salivary fungal mycobiome in 476 untreated incident NPC patients and 537 population-based controls using fungal internal transcribed spacer (ITS)-2 sequencing. The relationship between oral fungal mycobiome and the risk of NPC was assessed through bioinformatic and biostatistical analyses.
FINDINGS
We found that lower fungal alpha diversity was associated with an increased odds of NPC [lower vs. higher: observed features (adjusted odds ratio [OR] = 5.81, 95% confidence interval [CI] = 3.60-9.38); Simpson diversity (1.53, 1.03-2.29); Shannon diversity (2.03, 1.35-3.04)]. We also observed a significant difference in global fungal community patterns between cases and controls based on Bray-Curtis dissimilarity (P < 0.001). Carriage of oral fungal species, specifically, Saccharomyces cerevisiae, Candida tropicalis, Lodderomyces elongisporus, Candida albicans, and Fusarium poae, was associated with significantly higher odds of NPC, with ORs ranging from 1.56 to 4.66. Individuals with both low fungal and low bacterial alpha diversity had a profoundly elevated risk of NPC.
INTERPRETATION
Our results suggest that dysbiosis in the oral mycobiome, characterized by a loss of fungal community diversity and overgrowth of several fungal organisms, is associated with a substantially increased risk of NPC.
FUNDING
This work was funded by the US National Institutes of Health, the Swedish Research Council, the High-level Talents Research Start-up Project of Fujian Medical University, and the China Scholarship Council.
Topics: Humans; Nasopharyngeal Carcinoma; Dysbiosis; Case-Control Studies; Mycobiome; Saccharomyces cerevisiae; Nasopharyngeal Neoplasms
PubMed: 37776725
DOI: 10.1016/j.ebiom.2023.104813 -
European Journal of Medical Research Oct 2023For patients with locally advanced nasopharyngeal cancer (LA-NPC), concurrent chemoradiotherapy (CCRT) is the standardized treatment. However, whether a weekly or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
For patients with locally advanced nasopharyngeal cancer (LA-NPC), concurrent chemoradiotherapy (CCRT) is the standardized treatment. However, whether a weekly or triweekly cisplatin regimen should be used during CCRT is controversial. Therefore, we conducted this meta-analysis to explore differences in the effects and toxicities of the two regimens.
METHODS
We searched PubMed, Embase, and the Cochrane Library (until June 10, 2022). We evaluated overall survival (OS), distant metastasis-free survival (DMFS), locoregional recurrence-free survival (LRFS), disease-free survival (DFS) and grade ≥ 3 adverse events. The effect indices were hazard ratios (HRs) and odds ratios (ORs), and Review Manager software 5.4 (RevMan 5.4) was used for computations.
RESULTS
We identified 7 studies in our analysis. There was no significant difference in OS (HR = 1.00, 95% CI 0.73-1.38, P = 0.99), DMFS (HR = 0.84, 95% CI 0.58-1.22, P = 0.36), LRFS (HR = 0.91, 95% CI 0.63-1.32, P = 0.62) or DFS (HR = 0.93, 95% CI 0.56-1.56; P = 0.78) between the weekly and triweekly cisplatin regimens. We found that the weekly cisplatin regimen was more likely to cause grade ≥ 3 hematological toxicity events than the triweekly cisplatin regimen. In addition, subgroup analyses revealed that patients undergoing CCRT and CCRT plus adjuvant chemotherapy (AC) had similar OS or DFS.
CONCLUSION
Weekly and triweekly cisplatin regimens had similar efficacy for LA-NPC. The triweekly regimen may replace the weekly regimen for LA-NPC because of lower toxicity. Larger data accumulation and more multicenter clinical trials may be needed to verify these results.
Topics: Humans; Cisplatin; Nasopharyngeal Neoplasms; Nasopharyngeal Carcinoma; Chemoradiotherapy; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Multicenter Studies as Topic
PubMed: 37794519
DOI: 10.1186/s40001-023-01297-y -
Cell Communication and Signaling : CCS Jul 2023Malignant tumours area leading cause of death globally, accounting for approximately 13% of all deaths. A detailed understanding of the mechanism(s) of the occurrence... (Review)
Review
Malignant tumours area leading cause of death globally, accounting for approximately 13% of all deaths. A detailed understanding of the mechanism(s) of the occurrence and development of malignant tumours and identification of relevant therapeutic targets are therefore key to tumour treatment. tsRNAs(tRNA-derived small RNAs)-also known as TRFs (tRNA-derived fragments), tiRNAs (tRNA-derived stress-induced RNAs), tRNA halves, etc.-are a recently identified class of small noncoding RNAs that are generated from mature tRNA or tRNA precursors through cleavage by enzymes such as angiogenin, Dicer, RNase Z, and RNase P. Several studies have confirmed that dysregulation of tsRNAs is closely related to the tumorigenesis of breast cancer, nasopharyngeal cancer, lung cancer, and so on. Furthermore, research indicates that tsRNAs can be used as clinical diagnostic markers and therapeutic targets for cancer. In our review, we summarized the recent research progress on the role and clinical application of tsRNAs in tumorigenesis and progression. Video Abstract.
Topics: Humans; Nasopharyngeal Neoplasms; RNA; RNA, Transfer; Lung Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 37480078
DOI: 10.1186/s12964-023-01199-w -
Critical Reviews in Oncology/hematology Oct 2023We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment in recurrent/metastatic nasopharyngeal... (Review)
Review
We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR treatment in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) patients who progressed to previous anti-PD1 therapy. Enrolled patients were divided into a combination group and a chemotherapy only group. A total of 145 patients were enrolled. The median progress-free survival (mPFS) was 7.9 months and 4.4 months, respectively for the two groups. The combination group exhibited significantly longer PFS (HR=0.363, p < 0.001), and better disease control ratio (DCR, p = 0.022) compared with the chemotherapy group. Among the combination group, longer PFS was found in those patients who received different PD1 inhibitor from prior therapy, reached object response rate (ORR) from prior anti-PD1 therapy, and EBV DNA ≤ 1500 copy/ml before therapy, comparing to the corresponding other patients. R/M NPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with anti-angiogenesis or anti-EGFR agents.
Topics: Humans; Nasopharyngeal Carcinoma; Immunotherapy; Immune Checkpoint Inhibitors; Nasopharyngeal Neoplasms
PubMed: 37633346
DOI: 10.1016/j.critrevonc.2023.104113 -
Cancer Biology & Therapy Dec 2024N6-methyladenosine (m6A) is the most predominant RNA epigenetic regulation in eukaryotic cells. Numerous evidence revealed that m6A modification exerts a crucial role in...
N6-methyladenosine (m6A) is the most predominant RNA epigenetic regulation in eukaryotic cells. Numerous evidence revealed that m6A modification exerts a crucial role in the regulation of tumor microenvironment (TME) cell infiltration in several tumors. Nevertheless, the potential role and mechanism of m6A modification in nasopharyngeal carcinoma (NPC) remains unknown. mRNA expression data and clinical information from GSE102349, and GSE53819 datasets obtained from Gene Expression Omnibus (GEO) was used for differential gene expression and subsequent analysis. Consensus clustering was used to identify m6A-related molecular patterns of 88 NPC samples based on prognostic m6A regulators using Univariate Cox analysis. The TME cell-infiltrating characteristics of each m6A-related subclass were explored using single-sample gene set enrichment (ssGSEA) algorithm and CIBERSORT algotithm. DEGs between two m6A-related subclasses were screened using edgeR package. The prognostic signature and predicated nomogram were constructed based on the m6A-related DEGs. The cell infiltration and expression of prognostic signature in NPC was determined using immunohistochemistry (IHC) analysis. Chi-square test was used to analysis the significance of difference of the categorical variables. And survival analysis was performed using Kaplan-Meier plots and log-rank tests. The NPC samples were divided into two m6A-related subclasses. The TME cell-infiltrating characteristics analyses indicated that cluster 1 is characterized by immune-related and metabolism pathways activation, better response to anit-PD1 and anti-CTLA4 treatment and chemotherapy. And cluster 2 is characterized by stromal activation, low expression of HLA family and immune checkpoints, and a worse response to anti-PD1 and anti-CTLA4 treatment and chemotherapy. Furthermore, we identified 1558 DEGs between two m6A-related subclasses and constructed prognostic signatures to predicate the progression-free survival (PFS) for NPC patients. Compared to non-tumor samples, REEP2, TMSB15A, DSEL, and ID4 were upregulated in NPC samples. High expression of REEP2 and TMSB15A showed poor survival in NPC patients. The interaction between REEP2, TMSB15A, DSEL, ID4, and m6A regulators was detected. Our finding indicated that m6A modification plays an important role in the regulation of TME heterogeneity and complexity.
Topics: Humans; Epigenesis, Genetic; Nasopharyngeal Carcinoma; Tumor Microenvironment; Nasopharyngeal Neoplasms; Adenine
PubMed: 38532632
DOI: 10.1080/15384047.2024.2333590 -
International Immunopharmacology Dec 2023The treatment of nasopharyngeal carcinoma (NPC) is currently based on concurrent chemoradiotherapy. The prognosis of early NPC is better, while the prognosis of advanced... (Review)
Review
BACKGROUND
The treatment of nasopharyngeal carcinoma (NPC) is currently based on concurrent chemoradiotherapy. The prognosis of early NPC is better, while the prognosis of advanced NPC is poor. Immunotherapy is becoming increasingly commonly employed in clinical practice as a new strategy for treating malignant tumors. It has shown promising results in the treatment of certain malignant tumors, making it a current clinical research hotspot.
METHODS
This review summarizes the current immunotherapy on NPC, highlighting the application of immunotherapy and radiotherapy in the treatment of NPC.
RESULTS
X-rays can either increase or suppress anti-tumor immune responses through various pathways and mechanisms. Immune checkpoint inhibitors can usually enhance X-ray-induced anti-tumor immune responses. Detecting the immune checkpoint markers and tumor mutation markers, and the functional status of effector cells in patients can aid in the development of individualized treatment that improves the treatment efficacy with reducing drug resistance and adverse reactions. The development of a multivalent vaccine for NPC will help improve the efficacy of the vaccine. Combining techniques that increase the tumor antigens release, such as radiotherapy and oncolytic virus vaccines, may enhance the ability of the immune response.
CONCLUSIONS
To shed further light on the application of immunotherapy in NPC, large pooled studies must accumulate sufficient cases with detailed exposure data.
Topics: Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Immunotherapy; Chemoradiotherapy; Biomarkers, Tumor
PubMed: 37871379
DOI: 10.1016/j.intimp.2023.111094