To investigate prognostic-related gene signature based on DNA damage repair and tumor microenvironment statue in human papillomavirus 16 negative (HPV16-) head and neck squamous cell carcinoma (HNSCC).For the RNA-sequence matrix in HPV16- HNSCC in the Cancer Genome Atlas (TCGA) cohort, the DNA damage response (DDR) and tumor microenvironment (TM) status of each patient sample was estimated by using the ssGSEA algorithm. Through bioinformatics analysis in DDR_high/TM_high (n = 311) and DDR_high/TM_low (n = 53) groups, a survival-related gene signature was selected in the TCGA cohort. Two independent external validation cohorts (GSE65858 (n = 210) and GSE41613 (n = 97)) with HPV16- HNSCC patients validated the gene signature. Correlations among the clinical-related hub differentially expressed genes (DEGs) and infiltrated immunocytes were explored with the TIMER2.0 server. Drug screening based on hub DEGs was performed using the CellMiner and GSCALite databases. The loss-of-function studies were used to evaluate the effect of screened survival-related gene on the motility of HPV- HNSCC cells in vitro.A high DDR level (P = 0.025) and low TM score (P = 0.012) were independent risk factors for HPV16- HNSCC. Downregulated expression of ALOX12B or SPRR1A was associated with poor survival rate and advanced cancer stages. The pathway enrichment analysis showed the DDR_high/TM_low samples were enriched in glycosphingolipid biosynthesis-lacto and neolacto series, glutathione metabolism, platinum drug resistance, and ferroptosis pathways, while the DDR_high/TM_low samples were enriched in Th17 cell differentiation, Neutrophil extracellular trap formation, PD - L1 expression and PD - 1 checkpoint pathway in cancer. Notably, the expression of ALOX12B and SPRR1A were negatively correlated with cancer-associated fibroblasts (CAFs) infiltration and CAFs downstream effectors. Sensitivity to specific chemotherapy regimens can be derived from gene expressions. In addition, ALOX12B and SPRR1A expression was associated with the mRNA expression of insulin like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), mammalian target of rapamycin (MTOR), and eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) in HPV negative HNSCC. Down-regulation of ALOX12B promoted HPV- HNSCC cells migration and invasion in vitro.ALOX12B and SPRR1A served as a gene signature for overall survival in HPV16- HNSCC patients, and correlated with the amount of infiltrated CAFs. The specific drug pattern was determined by the gene signature.
Abstract Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT–qPCR validation and selection using a machine learning method in the training cohort ( n = 177). This nine-lncRNA signature classifies patients into high and low risk groups, which have significantly different distant metastasis-free survival. Validations in the Guangzhou internal ( n = 177) and Guilin external ( n = 150) cohorts yield similar results, confirming that the signature is an independent risk factor for distant metastasis and outperforms anatomy-based metrics in identifying patients with high metastatic risk. Integrative analyses show that this nine-lncRNA signature correlates with immune activity and lymphocyte infiltration, which is validated by digital pathology. Our results suggest that the immune-associated nine-lncRNA signature can serve as a promising biomarker for metastasis prediction in LA-NPC.
Abstract Background Nearly 90% locoregionally advanced nasopharyngeal carcinoma (LANPC) responds to induction chemotherapy (IC) with significant tumor volume shrinkage. Radiotherapy always follows IC, and reduced volume has been proposed. However, the efficacy and safety of reduced‐volume radiotherapy is uncertain. Methods In this multi‐center, noninferiority, randomized, controlled trial, patients with LANPC who completed IC were randomly assigned (1:1) to receive reduced‐volume radiotherapy based on post‐IC tumor volume (Post‐IC group) or conventional volume radiotherapy based on pre‐IC tumor volume (Pre‐IC group). The primary endpoint was locoregional relapse‐free survival, with a noninferiority margin of 8%. Secondary endpoints comprised adverse events, and quality of life (QoL). Results Between August 7, 2020, and May 27, 2022, 445 patients were randomly assigned to Post‐IC ( n = 225) or Pre‐IC ( n = 220) groups. The average volume receiving radical dose was 66.6 cm 3 in Post‐IC group versus 80.9 cm 3 . After a median follow‐up of 40.4 months, the 3‐year locoregional relapse‐free survival was 91.5% in the Post‐IC group versus 91.2%, with a difference of 0.3% (95% confidence interval −4.9% to 5.5%). The incidence of grade 3‐4 radiation‐related toxicity was lower in the Post‐IC group including: acute mucositis (19.8% vs 34.1%), late otitis media (9.5% vs 20.9%) and late dry month (3.6% vs 9.5%). The Post‐IC group had better QoL for global health status, physical functioning, emotional functioning, dry mouth and sticky saliva. Conclusions In this trial, reduced‐volume radiotherapy was noninferior to conventional volume radiotherapy in locoregional relapse‐free survival, and was associated with lower toxicities and improved QoL. (ClinicalTrials.gov identifier NCT04384627).
Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment.
Despite docetaxel combined with cisplatin and 5-fluorouracil (TPF) being the established treatment for advanced nasopharyngeal carcinoma (NPC), there are patients who do not respond positively to this form of therapy. However, the mechanisms underlying this lack of benefit remain unclear. DCAF7 is identified as a chemoresistance gene attenuating the response to TPF therapy in NPC patients. DCAF7 promotes the cisplatin resistance and metastasis of NPC cells in vitro and in vivo. Mechanistically, DCAF7 serves as a scaffold protein that facilitates the interaction between USP10 and G3BP1, leading to the elimination of K48-linked ubiquitin moieties from Lys76 of G3BP1. This process helps prevent the degradation of G3BP1 via the ubiquitin‒proteasome pathway and promotes the formation of stress granule (SG)-like structures. Moreover, knockdown of G3BP1 successfully reversed the formation of SG-like structures and the oncogenic effects of DCAF7. Significantly, NPC patients with increased levels of DCAF7 showed a high risk of metastasis, and elevated DCAF7 levels are linked to an unfavorable prognosis. The study reveals DCAF7 as a crucial gene for cisplatin resistance and offers further understanding of how chemoresistance develops in NPC. The DCAF7-USP10-G3BP1 axis contains potential targets and biomarkers for NPC treatment.
In the present study, ten novel microsatellite markers were developed from an enriched-(CA) 13 genomic library of Epinephelus akaara.The mean number of alleles per locus was 21.6, with a range of 12 to 33.Observed heterozygosity ranged from 0.767 to 0.967, and expected heterozygosity ranged from 0.831 to 0.975, with mean values of 0.877 and 0.923, respectively.Among the ten loci, three loci deviated from Hardy-Weinberg equilibrium after sequential Bonferroni's correction.These polymorphic microsatellite markers may be useful for studies on the population genetics of E. akaara.
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