Abstract Background Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area. Methods HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0. Results HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10 −4 ). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles. Conclusions Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC.
Sleep health and other lifestyle behaviours are gaining increasing attention in public health, particularly for cancer prevention, but a comprehensive assessment is lacking. The study included 380,042 UK Biobank participants. A healthy sleep score was constructed based on five sleep factors: chronotype, sleep duration, insomnia, snoring, and daytime dozing. A healthy lifestyle score was constructed based on four lifestyle factors: smoking, alcohol consumption, diet and physical activity. The effect of healthy sleep and lifestyle on cancer risk was examined by Cox proportional hazard models. Both healthy sleep and lifestyle patterns were significantly associated with a reduced risk of overall cancer and specific cancer sites. Participants with healthy sleep and lifestyle patterns had a lower risk of overall cancer (HR = 0.72, 95% CI = 0.68-0.77), liver cancer (HR = 0.53, 95% CI = 0.31-0.90), bladder cancer (HR = 0.61, 95% CI = 0.47-0.79), lung cancer (HR = 0.22, 95% CI = 0.19-0.27), and colorectal cancer (HR = 0.80, 95% CI = 0.66-0.96) compared to those with unhealthy patterns. Our findings highlight the importance of public health education and interventions to improve sleep and other lifestyle behaviours for cancer prevention.
We sincerely appreciate Mark T. L. TAN and his co-workers for their comments “The Hunt for the Perfect Biomarker in Nasopharyngeal Carcinoma—the RRAS “race” beyond Epstein-Barr virus?” on our study titled “Identification of RRAS gene related to nasopharyngeal carcinoma based on pathway and network-based analyses”. Nasopharyngeal carcinoma (NPC) is an endemic tumor closely associated with Epstein barr virus (EBV) (1).
Deregulated microRNAs play an important role in the development and progression of various types of cancer. In our previous study, we observed that microRNA‑342‑3p (miR‑342‑3p) was one of the most markedly downregulated microRNAs in two nasopharyngeal carcinoma (NPC) cell lines compared to non‑neoplastic cells by using whole genome small RNA sequencing. In the present study, we confirmed that the expression of miR‑342‑3p was significantly reduced in NPC tissues compared with normal nasopharyngeal epithelial tissues. Overexpression of miR‑342‑3p inhibited proliferation, epithelial‑mesenchymal transition (EMT), migration and invasiveness of NPC cells. In addition, we observed that Cdc42, a Rho GTPase family member involved in cell proliferation and metastasis, is a direct target of miR‑342‑3p. Additionally, ML141, a small‑molecule inhibitor of Cdc42, efficiently suppressed the invasion of NPC cells compared with the control cells. Finally, we analyzed NPC tissues derived from 10 NPC patients and subjected them to quantitative RT‑PCR and immunohistochemistry assays for concomitant determination of the expression levels of miR‑342‑3p and Cdc42. Our results revealed that miR‑342‑3p levels were significantly inversely correlated with the protein levels of its target Cdc42. The results of the present study indicated that miR‑342‑3p inhibited NPC tumor growth and invasion by directly targeting the Cdc42 pathway.
Accumulating evidence has shown that circular RNAs (circRNAs) are involved in gastric cancer (GC) tumorigenesis. However, specific functional circRNAs in GC remain to be discovered, and their underlying mechanisms remain to be elucidated.
Nasopharyngeal carcinoma (NPC) is a highly aggressive neoplasm mainly distributed in the eastern and southeastern parts of Asia. NPC has a poor prognosis among head and neck cancers, and molecular-targeted therapies showed limited clinical efficacy.We reviewed publications in the PubMed database and extracted genes associated with NPC. The online tool WebGestalt was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for these genes. Next, the two parameters, Jaccard Coefficient (JC) and Overlap Coefficient (OC), were used to analyze the crosstalk of each pair of selected pathways. The new NPC-related genes were predicted by protein-protein interaction (PPI) network combined with hub genes extraction. Western blotting, qRT-PCR, and immunohistochemistry (IHC) were used to detect the expression of candidate genes in NPC cells and tissues, and cellular function assays were used to explore the effects of genes on NPC cells.A total of 552 genes were identified and used to build an NPC-related gene set (NPCgset). Pathways enriched in KEGG pathway analysis were further used for crosstalk analysis and were grouped into two modules: one was related to the carcinogenesis process, and the other was correlated with the immune response. Eight genes from the NPCgset were selected to build a PPI network, and two hub genes PIK3CA and AKT1 were chosen. Proteins interacting with PIK3CA were analyzed; among them, the expression of RRAS was down-regulated in NPC and associated with poor prognosis of NPC patients. Furthermore, RRAS suppressed proliferation, invasion and the epithelial-mesenchymal transformation (EMT) of the HK1 and 5-8F cell lines.Our study may help to explore the biological processes underlying NPCgset and suggests that RRAS may act as a tumor suppressor gene in NPC.
Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.
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