Prognosis Of Head And Neck Squamous Cell Carcinoma Patients Research Articles

Identification of PATL1 as a prognostic and immunotherapeutic predictive factor for nasal-type natural killer/T-cell lymphoma and head and neck squamous cell carcinoma

This research examines the function of protein associated with topoisomerase II homolog 1 (PATL1) in nasal-type natural killer/T-cell lymphoma (NKTCL) and head and neck squamous cell carcinoma (HNSCC). We analyzed bulk RNA-seq data from NKTCL, nasal polyps, and normal nasal mucosa, identifying 439 differentially expressed genes. Machine learning algorithms highlighted PATL1 as a hub gene. PATL1 exhibited significant upregulation in NKTCL and HNSCC tumor samples in comparison to normal tissues, showing high diagnostic accuracy (AUC = 1.000) for NKTCL. Further analysis of local hospital data identified PATL1 as an independent prognostic risk factor for NKTCL. Data analysis of TCGA and GEO datasets revealed that high PATL1 expression correlated with poorer prognosis in HNSCC patients (p < 0.05). We also constructed a PATL1-based nomogram, which emerged as an independent prognostic predictor for HNSCC after addressing missing values. Additionally, we found a strong correlation between PATL1 and various immune cell infiltrates (e.g., activated.CD4 T cell), and a significant association with the expression of 37 immune checkpoints genes (e.g., CTLA4, PDCD1) and 20 N6-methyladenosine-related genes (e.g., ZC3H13, METTL3) (all p < 0.05). Both TCIA and TIDE algorithms suggested that PATL1 could potentially predict immunotherapy efficacy (p < 0.05). Cellular experiments demonstrated that transfection with a silencing plasmid of PATL1 significantly inhibited the malignant behaviors of SNK6 and FaDu cell lines(p < 0.05). In conclusion, our findings suggest that PATL1 may serve as a valuable prognostic and predictive biomarker in NKTCL and HNSCC, highlighting its significant role in these cancers.

Systematic analysis of expression and prognostic significance for MCM family in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is a common malignant tumor in the world and has a poor prognosis. The family of minichromosome maintenance proteins (MCM) improves the stability of genome replication by inhibiting the rate of DNA replication in eukaryotic cells, thus, small changes in physiological MCM levels would increase the instability of gene replication and increase the incidence of tumor formation, most of which are significantly elevated in multiple cancers. However, the expression of different MCM families in HNSC and their prognostic value remain unclear. ONCOMINE and GEPIA databases were used to analyze the expression of MCMs in HNSC. The Kaplan-Meier plotter database was used to identify molecules with prognostic values. We collected 77 HNSC tissues and 50 normal tissues to validate the results of the bioinformatics analysis by immunohistochemical staining. The expression of MCM3, MCM5 and MCM6 in mRNA and protein levels were higher in HNSC. Moreover, the increased expression of MCM3, MCM5 and MCM6 in mRNA and protein levels predicted better prognosis of HNSC patients. Furthermore, multivariate analysis showed that high expressions of MCM3, MCM5 and MCM6 in protein level may be independent prognostic factors for HNSC patients. The results of this study indicated that MCM3, MCM5 and MCM6 play an important role in occurrence and development in HNSC and might be risk factors for the survival of HNSC patients.

Identification of splicing factors signature predicting prognosis risk and the mechanistic roles of novel oncogenes in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is the most frequent subtype of head and neck cancer, generally with a poor prognosis and limited therapeutic options due to its highly heterogeneous malignancy. In this study, we screened functional splicing regulatory RNA binding proteins (RBPs) that were closely related with the prognosis of HNSCC patients and showed significant expression differences between HNSCC tumors and normal tissues. Based on this finding, we chose six candidate genes (HNRNPC, ZCRB1, RBM12B, SF3A2, SF3B3, and SRSF11) to generate a prognostic prediction model and validated the accuracy of the prognostic model for predicting patient survival outcomes. We found that the risk score predicted by our model can serve as an independent prognostic predictor. Notably, HNSCC tumors showing higher expression of SF3B3, HNRNPC, or ZCRB1 possessed higher risk scores in the discovered prediction model. The investigation of the underlying mechanism validated that knockdown of SF3B3, HNRNPC, and ZCRB1 separately induced a substantial impairment of HNSCC cell survival. Conversely, overexpression of each of the three genes promoted tumor cellular proliferation. High throughput RNA sequencing analysis revealed that changes in the expression of SF3B3 and HNRNPC remarkably affected alternative splicing of genes related to cell cycle regulation, whereas the depletion of ZCRB1 contributed to aberrant splicing events involving in DNA damage response. In addition, the prognostic prediction model's risk score was demonstrated to be related with the immune infiltration score. Particularly, SF3B3 has a negative correlation with CD8A expression. Therefore, our findings provide promising prognosis predictors and potential therapeutic targets for better treatment efficacy of HNSCC.

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification

Existing studies have underscored the pivotal role of N-acetyltransferase 10 (NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma (HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1 (RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6 (ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac4C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel tRNA-ac4C modification sites, thereby providing a potent sequencing tool for tRNA-ac4C research. Our findings expand the repertoire of tRNA ac4C modifications and identify a role of tRNA ac4C in the regulation of mRNA translation in HNSCC.

Development and Validation of a Pathomics Model Using Machine Learning to Predict CXCL8 Expression and Prognosis in Head and Neck Cancer.

The necessity to develop a method for prognostication and to identify novel biomarkers for personalized medicine in patients with head and neck squamous cell carcinoma (HNSCC) cannot be overstated. Recently, pathomics, which relies on quantitative analysis of medical imaging, has come to the forefront. CXCL8, an essential inflammatory cytokine, has been shown to correlate with overall survival (OS). This study examined the relationship between CXCL8 mRNA expression and pathomics features and aimed to explore the biological underpinnings of CXCL8. Clinical information and transcripts per million mRNA sequencing data were obtained from The Cancer Genome Atlas (TCGA)-HNSCC dataset. We identified correlations between CXCL8 mRNA expression and patient survival rates using a Kaplan-Meier survival curve. A retrospective analysis of 313 samples diagnosed with HNSCC in the TCGA database was conducted. Pathomics features were extracted from hematoxylin and eosin-stained images, and then the minimum redundancy maximum relevance, with recursive feature elimination (mRMR-RFE) method was applied, followed by screening with the logistic regression algorithm. Kaplan-Meier curves indicated that high expression of CXCL8 was significantly associated with decreased OS. The logistic regression pathomics model incorporated 16 radiomics features identified by the mRMR-RFE method in the training set and demonstrated strong performance in the testing set. Calibration plots showed that the probability of high gene expression predicted by the pathomics model was in good agreement with actual observations, suggesting the model's high clinical applicability. The pathomics model of CXCL8 mRNA expression serves as an effective tool for predicting prognosis in patients with HNSCC and can aid in clinical decision-making. Elevated levels of CXCL8 expression may lead to reduced DNA damage and are associated with a pro-inflammatory tumor microenvironment, offering a potential therapeutic target.

Aberrated PSMA1 expression associated with clinicopathological features and prognosis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a globally prevalent cancer with significant mortality rates. OSCC a predominant subtype of head and neck squamous cell carcinoma (HNSCC), poses a substantial health burden. Despite advancements in diagnosis and therapy, OSCC prognosis remains poor. The 26S proteasome, a cellular protein degradation complex, is associated with cancer, including PSMA1, a proteasomal subunit, which is upregulated in various cancers. We analyzed PSMA1 expression using TCGA data, validated it in OSCC samples using real-time PCR, and explored its role through various databases. Tumor and adjacent normal tissues from OSCC patients were examined, and PSMA1 expression was analyzed. Survival analysis assessed the impact of PSMA1 on patient outcomes, while immune infiltration was examined using the TIMER database. GeneMANIA, STRING, and Metascape were utilized for gene interaction and pathway analysis. PSMA1 was significantly upregulated in OSCC and HNSCC. Its overexpression correlated with advanced clinicopathological features and poorer prognosis in HNSCC patients. PSMA1 expression is also related to immune cell infiltration. Gene interaction analysis revealed PSMA1 involvement in proteolysis regulation, suggesting its potential as a therapeutic target. PSMA1 upregulation in HNSCC association with adverse clinicopathological features and prognosis underscores its potential significance. Further research is warranted to elucidate its molecular mechanisms and therapeutic potential in OSCC management.

Comprehensive Investigation of m6A Regulators for Prognosis in Head and Neck Squamous Cell Carcinoma.

The early detection of head and neck squamous cell carcinoma (HNSCC) has an important impact on the clinical prognosis. N6-methyladenosine (m6A) is involved in the post-transcriptional regulation of tumorigenesis and development. In this study, the prognosis and biological functions of m6A regulator targets in HNSCC were explored. RNA-Seq expression data and clinical information from TCGA-HNSCC and GSE23036 datasets were collected. The mRNA levels of IGF2BP2 and IGF2BP3 in tumor tissues were significantly up-regulated. Differential expression and functional enrichment analysis of potential targets for IGF2BP2 and IGF2BP3 obtained from the m6A2Target database showed that they were significantly enriched in cell cycle-related pathways. The Cox regression analysis was performed to establish a three-mRNA signature including PLAU, LPIN1 and AURKA. The prognostic effect was verified in the external dataset GSE41613. Further studies revealed that the three-mRNA signature was significantly associated with survival in the clinical subgroup. The ROC curve, Harrell consistency index and decision curve comparison used to compare the predictive effect of the three-mRNA signature and the other signatures in previous studies showed that the three-mRNA signature had better predictive effect on the prognosis of HNSCC patients. The three-mRNA signature expression were verified in HNSCC cell lines with qRT-PCR and Western blot. Sequence analysis showed that m6A-modification sites existed on PLAU, LPIN1 and AURKA genes. In conclusion, the three-mRNA signature has been proved to be useful on evaluating the prognosis and contributing to the personalized treatment of HNSCC, and IGB2BP2/3 were related to the cell cycle in HNSCC.

The Potential of Lipid Droplet-associated Genes as Diagnostic and Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma.

The role of lipid droplets (LDs) and lipid droplet-associated genes (LD-AGs) remains unclear in head and neck squamous cell carcinoma (HNSCC). This study aimed to investigate LDs in HNSCC and identify LD-AGs essential for the diagnosis and prognosis of HNSCC patients. The LDs in the HNSCC and normal cell lines were stained with oil red O. Bioinformatic analysis was used to find LD-AGs in HNSCC that had diagnostic and prognostic significance. LDs accumulation was increased in HNSCC cell lines compared with normal cell lines (P<0.05). Fifty-three differentially expressed genes, including 34 upregulated and 19 downregulated, were found in HNSCC based on the TCGA platform (P<0.05). Then, 53 genes were proved to be functionally enriched in lipid metabolism and LDs. Among them, with an AUC value > 0.7, 34 genes demonstrated a high predictive power. Six genes (AUP1, CAV1, CAV2, CAVIN1, HILPDA, and SQLE) out of 34 diagnostic genes were linked to overall survival in patients with HNSCC (P<0.05). The significant prognostic factors AUP1, CAV1, CAV2, and SQLE were further identified using the univariate and multivariate cox proportional hazard models (P<0.05). The protein expression of CAV2 and SQLE was significantly increased in the HNSCC tissue compared to normal tissues (P<0.05). Finally, the knockdown of the four LD-AGs decreased LDs accumulation, respectively. Increased LDs accumulation was a hallmark of HNSCC, and AUP1, CAV1, CAV2, and SQLE were discovered as differentially expressed LD-AGs with diagnostic and prognostic potential in HNSCC.

Potential Role of the Intratumoral Microbiota in Prognosis of Head and Neck Cancer.

The tumor microbiome, a relatively new research field, affects tumor progression through several mechanisms. The Cancer Microbiome Atlas (TCMA) database was recently published. In the present study, we used TCMA and The Cancer Genome Atlas and examined microbiome profiling in head and neck squamous cell carcinoma (HNSCC), the role of the intratumoral microbiota in the prognosis of HNSCC patients, and differentially expressed genes in tumor cells in relation to specific bacterial infections. We investigated 18 microbes at the genus level that differed between solid normal tissue (n = 22) and primary tumors (n = 154). The tissue microbiome profiles of Actinomyces, Fusobacterium, and Rothia at the genus level differed between the solid normal tissue and primary tumors of HNSCC patients. When the prognosis of groups with rates over and under the median for each microbe at the genus level was examined, rates for Leptotrichia which were over the median correlated with significantly higher overall survival rates. We then extracted 35 differentially expressed genes between the over- and under-the-median-for-Leptotrichia groups based on the criteria of >1.5 fold and p < 0.05 in the Mann-Whitney U-test. A pathway analysis showed that these Leptotrichia-related genes were associated with the pathways of Alzheimer disease, neurodegeneration-multiple diseases, prion disease, MAPK signaling, and PI3K-Akt signaling, while protein-protein interaction analysis revealed that these genes formed a dense network. In conclusion, probiotics and specific antimicrobial therapy targeting Leptotrichia may have an impact on the prognosis of HNSCC.

HtrA3: a promising prognostic biomarker and therapeutic target for head and neck squamous cell carcinoma.

The dysregulation of the human high-temperature requirement A (HtrA) family of serine proteases is associated with many malignancies. However, there are few reports on HtrAs in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the expression, prognostic value, and biological functions of HtrAs in HNSCC. The RNA-sequencing data and clinical data of HNSCC were downloaded from The Cancer Genome Atlas (TCGA) database. The GSE30784 and GSE31056 datasets from the Gene Expression Omnibus (GEO) database were used for further verification. This study explored the differential expression of HtrAs and assessed their potential impact on the prognosis of HNSCC patients using a survival module. Correlations between clinical characteristics and HtrA expression levels were then explored using a Wilcoxon rank sum test. A Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed using "clusterProfile" in the R software. A Pearson/Spearman correlation test was applied to analyze the relationship between HtrAs and immune infiltration level/checkpoint genes. Validation of HtrA expression levels were carried out by RT-PCR and western blot in human squamous carcinoma cell lines (Fadu and Cal-27) and human non-tumorigenic bronchial epithelium cells (BEAS-2B). Finally, through cell transfection, CCK-8, Ki-67 immunofluorescence, and flow cytometry assays, the effect of HtrA3 knockdown on the malignant biological behavior of HNSCC cells was explored. The gene expression levels of HtrAs were significantly upregulated and associated with patient age, TNM stage, clinical stage, and TP53 mutation status in the TCGA-HNSCC cohort. High expressions of HtrA1/3 were associated with shorter overall survival, shorter progress-free interval, and lower disease-specific survival in HNSCC. A nomogram for HtrAs was constructed and validated. HtrA-related genes were significantly enriched in the immune response and cell apoptosis pathway. In addition, the expression of HtrAs showed significant correlations with B cells, M cells, DC cell infiltration, and immune infiltration checkpoint (CD276, TNFRSF14). Validation of HtrA expression was carried out by RT-PCR and western blot. Results of in vitro experiments indicated that HtrA3 gene knockdown inhibits the proliferation of FaDu and Cal-27 cells while concurrently promoting apoptosis. HtrA3 shows significant potential as both a prognostic marker and a promising therapeutic target for HNSCC, highlighting its relevance and importance in future research and potential clinical applications.

A systematic review and meta-analysis of predictive and prognostic models for outcome prediction using positron emission tomography radiomics in head and neck squamous cell carcinoma patients.

Positron emission tomography (PET) images of head and neck squamous cell carcinoma (HNSCC) patients can assess the functional and biochemical processes at cellular levels. Therefore, PET radiomics-based prediction and prognostic models have the potentials to understand tumour heterogeneity and assist clinicians with diagnosis, prognosis and management of the disease. We conducted a systematic review of published modelling information to evaluate the usefulness of PET radiomics in the prediction and prognosis of HNSCC patients. We searched bibliographic databases (MEDLINE, Embase, Web of Science) from 2010 to 2021 and considered 31 studies with pre-defined inclusion criteria. We followed the CHARMS checklist for data extraction and performed quality assessment using the PROBAST tool. We conducted a meta-analysis to estimate the accuracy of the prediction and prognostic models using the diagnostic odds ratio (DOR) and average C-statistic, respectively. Manual segmentation method followed by 40% of the maximum standardised uptake value (SUVmax ) thresholding is a commonly used approach. The area under the receiver operating curves of externally validated prediction models ranged between 0.60-0.87, 0.65-0.86 and 0.62-0.75 for overall survival, distant metastasis and recurrence, respectively. Most studies highlighted an overall high risk of bias (outcome definition, statistical methodologies and external validation of models) and high unclear concern in terms of applicability. The meta-analysis showed the estimated pooled DOR of 6.75 (95% CI: 4.45, 10.23) for prediction models and the C-statistic of 0.71 (95% CI: 0.67, 0.74) for prognostic models. Both prediction and prognostic models using clinical variables and PET radiomics demonstrated reliable accuracy for detecting adverse outcomes in HNSCC, suggesting the prospect of PET radiomics in clinical settings for diagnosis, prognosis and management of HNSCC patients. Future studies of prediction and prognostic models should emphasise the quality of reporting, external model validation, generalisability to real clinical scenarios and enhanced reproducibility of results.

Comprehensive analysis of the prognosis and biological significance of RORβ in head and neck squamous cell carcinoma.

Recent studies have shown that abnormal expression of the core circadian clock gene, retinoic acid-related orphan receptor β (RORβ ), is closely associated with the occurrence and progression of various malignant tumors. However, the expression and function of RORβ in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we comprehensively investigated the altered expression, clinical significance, prognostic value, and biological functions of RORβ in HNSC, as well as its correlation with changes in the tumor immune microenvironment. We found that RORβ expression was decreased in HNSC and 19 other cancers. Low RORβ expression was significantly associated with tumor size, clinical stage, and survival time in HNSC patients, indicating that it may have diagnostic and prognostic value in HNSCC. Epigenetic analysis showed that the promoter methylation level of RORβ was significantly higher in HNSCC compared to adjacent noncancerous tissues. Furthermore, RORβ hypermethylation was significantly associated with low expression levels of RORβ and poor prognosis in HNSCC patients (p < 0.05). Enrichment analysis found that RORβ was involved in immune system regulation and T-cell activation, as well as the PI3K/AKT and ECM receptors interaction pathways. In vitro assays revealed that RORβ regulated the proliferation, migration and invasion ability of HNSCC cells. Additionally, we found that RORβ expression was significantly correlated with changes in the tumor immune microenvironment, suggesting it may affect prognosis by regulating immune infiltration in HNSC patients. Therefore, RORβ may serve as a potential prognostic biomarker and therapeutic target for HNSCC patients.

Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been demonstrated to play a critical role in regulating cholesterol homeostasis and Tcell antitumor immunity. However, the expression, function, and therapeutic value of PCSK9 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we found that the expression of PCSK9 was upregulated in HNSCC tissues, and higher PCSK9 expression indicated poorer prognosis in HNSCC patients. We further found that pharmacological inhibition or siRNA downregulating PCSK9 expression suppressed the stemness-like phenotype of cancer cells in an LDLR-dependent manner. Moreover, PCSK9 inhibition enhanced the infiltration of CD8+ Tcells and reduced the myeloid-derived suppressor cells (MDSCs) in a 4MOSC1 syngeneic tumor-bearing mouse model, and it also enhanced the antitumor effect of anti-PD-1 immune checkpoint blockade (ICB) therapy. Together, these results indicated that PCSK9, a traditional hypercholesterolemia target, may be a novel biomarker and therapeutic target to enhance ICB therapy in HNSCC.

Identification of SLC2A3 as a prognostic indicator correlated with the NF-κB/EMT axis and immune response in head and neck squamous cell carcinoma

ABSTRACT SLC2A3 is an important member of the glucose transporter superfamily. It has been recently suggested that upregulation of SLC2A3 is associated with poor survival and acts as a prognostic marker in a variety of tumors. Unfortunately, the prognostic role of SLC2A3 in head and neck squamous cell carcinoma (HNSC) is less known. In the present study, we analyzed SLC2A3 expression in HNSC and its correlation with prognosis using TCGA and GEO databases. The results showed that SLC2A3 mRNA expression was higher in HNSC compared with adjacent normal tissues, which was validated with our 9 pairs of HNSC specimens. Moreover, high SLC2A3 expression predicted poor prognosis in HNSC patients. Mechanistically, GSEA revealed that high expression of SLC2A3 was enriched in epithelial-mesenchymal transition (EMT) and NF-κB signaling. In HNSC cell lines, SLC2A3 knockdown inhibited cell proliferation and migration. In addition, NF-κB P65 and EMT-related gene expression was suppressed upon SLC2A3 knockdown, indicating that SLC2A3 may play a preeminent role in the progression of HNSC through the NF-κB/EMT axis. Meanwhile, the expression of SLC2A3 was negatively correlated with immune cells, suggesting that SLC2A3 may be involved in the immune response in HNSC. The correlation between SLC2A3 expression and drug sensitivity was further assessed. In conclusion, our study demonstrated that SLC2A3 could predict the prognosis of HNSC patients and mediate the progression of HNSC via the NF-κB/EMT axis and immune responses.

Comprehensive analysis reveals CCDC60 as a potential biomarker correlated with prognosis and immune infiltration of head and neck squamous cell carcinoma.

Coiled-coil domain containing 60 (CCDC60) is a member of the CCDC family, which participates in the progression of many types of cancer. However, the prognostic value of CCDC60 in head and neck squamous cell carcinoma (HNSC) and its function in tumor immunity remain unclear. CCDC60 expression and its prognostic potential in HNSC were evaluated by bioinformatics approaches, which was validated in human HNSC samples. Genetic alteration analysis of CCDC60 and the underlying biological function of CCDC60 related co-expressed genes in HNSC were analyzed. The impact of CCDC60 on the regulation of immune infiltration in HNSC was comprehensively investigated. In vitro, a series of functional assays on CCDC60 were performed in HNSC cells. Our study has indicated that compared with the adjacent normal tissues, CCDC60 expression was considerably downregulated in HNSC tissues. High CCDC60 expression was connected with favorable outcome of HNSC patients, and its prognostic significance was examined by distinct clinical characteristics. We identified the CCDC60-related co-expression genes, which were mainly enriched in the NOD-like receptor signaling pathway associated with the inhibition of tumor growth, leading to a better prognosis of HNSC patients. In vitro, CCDC60 overexpression significantly inhibited the growth, migration and invasiveness but regulated cell cycle progression, and promoted cell adhesion of Fadu and Cal27 cells. Additionally, high CCDC60 expression had strong connections with the infiltrating levels of immune cells, immune marker sets, immunomodulators and chemokines in HNSC, suggesting that targeting CCDC60 could be a promising strategy to enhance the efficacy of immunotherapy for HNSC patients. Tumor suppressor CCDC60 may be identified as a prognostic and immune-related indicator in HNSC, which had the potential functions in regulating the immune infiltration of HNSC and improving the response to immunotherapy for HNSC patients.

Clinical significance and integrative analysis of the cuproptosis-associated genes in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSC) is a kind of malignant tumor originating from the oropharynx, larynx, nasopharynx and oral cavity. The incidence of HNSC is increasing and it is the sixth malignant tumor in the world at present. "Cuprotosis" is a novel cuper-dependent cell death mode that is closely related to mitochondrial respiration. Tumorigenesis is closely related to the dysregulation of cell death. However, the relationship between cuprotosis and HNSC remains unclear. Here, we investigated the association between 10 cuprotosis-associated genes (CAGs) and HNSC using multi-omics public data. We found that CAGs had abnormal expression and significant genetic changes in HNSC, especially CDKN2A with 54% mutation rate. Expression of CAGs significantly correlates with the prognosis of HNSC patients. Moreover, the CAGs expression is correlated with the immune checkpoints expression and immune cells infiltration. These CAGs expression was associated with multiple drugs sensitivity of cancer cells, such as cisplatin and docetaxel. These findings indicate that CAGs are likely to serve an essential role in the diagnosis, prognosis, immunotherapy and drug therapy prediction of HNSC.

The lncRNA XIST/miR-29b-3p/COL3A1 axis regulates central carbon metabolism in head and neck squamous cell carcinoma and is associated with poor tumor prognosis.

Recent evidence shows that COL3A1 promotes the progression of many types of cancer. The purpose of our study is to explore the correlation between COL3A1 and the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) and its potential mechanism. We initially screened the differentially expressed gene COL3A1 in The Cancer Genome Atlas (TCGA) database, and the association between the expression level of COL3A1, prognosis, and the clinical parameters of HNSCC patients was verified. A nomogram was constructed according to the multivariate analysis results. Next, a heatmap of COL3A1 co-expressed genes was constructed in TCGA database. The TargetScan database is used to explore the microRNAs (miRNA) related to COL3A1. The starBase database was used to explore and predict the long non-coding RNAs (lncRNAs) that the candidate miRNAs might bind to. Finally, the potential mechanism of action was investigated using Gene Set Enrichment Analysis (GSEA). COL3A1 expression is elevated in HNSCC tumor tissues, and HNSCC patients with high COL3A1 expression have worse prognostic factors. COL3A1 was positively correlated with the central carbon metabolism-related proteins: epidermal growth factor receptor (EGFR), phosphoglycerate mutase 1 (PGAM1), hexokinase 3 (HK3), and phosphofructokinase, platelet (PFKP). The TargetScan database showed that the best candidate miRNA for binding to the three prime untranslated region (3'UTR) end of COL3A1 mRNA was hsa-miR-29b-3p, which was negatively correlated with COL3A1. The starBase database showed that the lncRNA X Inactive Specific Transcript (lncRNA XIST) was the best candidate upstream non-coding RNA for regulating hsa-miR-29b-3p. GSEA showed that COL3A1 may be involved in the poor prognosis of HNSCC by participating in carbon metabolism, glucose metabolism, oxidative stress, and the Wingless-Type MMTV Integration Site Family (Wnt) and vascular endothelial growth factor A-vascular endothelial growth factor receptor 2 (VEGFA-VEGFR2) pathways. Low COL3A1 expression can be employed as a new HNSCC predictive biomarker, and the prognosis of HNSCC patients with lower COL3A1 expression can be greatly improved. At the same time, we found that the lncRNA XIST/miR-29b-3p/COL3A1 axis may regulate the central carbon metabolism of HNSCC and is associated with poor prognosis. These findings point to a potential target for developing HNSCC anticancer therapies.

Integrative analyses of biomarkers and pathways for metformin reversing cisplatin resistance in head and neck squamous cell carcinoma cells

ObjectivesIn this study, transcriptome sequencing were performed to elucidate the molecular mechanism by which metformin inhibits head and neck squamous cell carcinoma (HNSCC) cells progression and sensitizes HNSCC cells to chemotherapy. We aimed to propose a novel chemotherapeutic approach with high efficacy and few side effects and provide a new strategy for HNSCC treatment. DesignThe effects of metformin on the biological behaviors of HNSCC cells were validated by CCK8 cell proliferation assays, would healing assays and flow cytometric apoptosis assays. The appropriate metformin concentrations for the experimental pretreatment of HNSCC cells were selected based on experimental results, and the treated cells were subjected to transcriptome sequencing. After bioinformatics analysis and intersection with a post-chemotherapy resistance dataset from the GEO database numbered GSE102787, the genes were identified and used to predict potential metformin targets after functional enrichment analysis. ResultsMetformin significantly inhibited the proliferation and migration and induced the apoptosis of Cal27 and FaDu cells. A total of 284 genes that are potentially targeted by metformin during HNSCC cell sensitization were identified by bioinformatics, and ten hub genes with high connectivity were selected. In particular, Fen1 overexpression was associated with poor prognosis in HNSCC patients. ConclusionsOur study demonstrates that Fen1 is overexpressed in HNSCC tissues compared with normal tissues and that Fen1 overexpression is a poor prognostic factor in HNSCC patients. Metformin enhances the ability of cisplatin to inhibit HNSCC progression. Further studies are needed to explore the therapeutic value of Fen1 in HNSCC.

A meta-validated immune infiltration-related gene model predicts prognosis and immunotherapy sensitivity in HNSCC

BackgroundTumor microenvironment (TME) is of great importance to regulate the initiation and advance of cancer. The immune infiltration patterns of TME have been considered to impact the prognosis and immunotherapy sensitivity in Head and Neck squamous cell carcinoma (HNSCC). Whereas, specific molecular targets and cell components involved in the HNSCC tumor microenvironment remain a twilight zone.MethodsImmune scores of TCGA-HNSCC patients were calculated via ESTIMATE algorithm, followed by weighted gene co-expression network analysis (WGCNA) to filter immune infiltration-related gene modules. Univariate, the least absolute shrinkage and selection operator (LASSO), and multivariate cox regression were applied to construct the prognostic model. The predictive capacity was validated by meta-analysis including external dataset GSE65858, GSE41613 and GSE686. Model candidate genes were verified at mRNA and protein levels using public database and independent specimens of immunohistochemistry. Immunotherapy-treated cohort GSE159067, TIDE and CIBERSORT were used to evaluate the features of immunotherapy responsiveness and immune infiltration in HNSCC.ResultsImmune microenvironment was significantly associated with the prognosis of HNSCC patients. Total 277 immune infiltration-related genes were filtered by WGCNA and involved in various immune processes. Cox regression identified nine prognostic immune infiltration-related genes (MORF4L2, CTSL1, TBC1D2, C5orf15, LIPA, WIPF1, CXCL13, TMEM173, ISG20) to build a risk score. Most candidate genes were highly expressed in HNSCC tissues at mRNA and protein levels. Survival meta-analysis illustrated high prognostic accuracy of the model in the discovery cohort and validation cohort. Higher proportion of progression-free outcomes, lower TIDE scores and higher expression levels of immune checkpoint genes indicated enhanced immunotherapy responsiveness in low-risk patients. Decreased memory B cells, CD8+ T cells, follicular helper T cells, regulatory T cells, and increased activated dendritic cells and activated mast cells were identified as crucial immune cells in the TME of high-risk patients.ConclusionsThe immune infiltration-related gene model was well-qualified and provided novel biomarkers for the prognosis of HNSCC.

PLAU and LAMC2 can predict a poor prognosis in patients with HNSCC.

Objectives: Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck. However, the molecular mechanisms governing the development of HNSCC have not been fully elucidated. Materials and Methods: Differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) and GSE23036 datasets. Weighted gene coexpression network analysis (WGCNA) was used to reveal the correlations among genes and to search for significantly correlated gene modules. The expression levels of genes in HNSCC and normal samples according to antibody-based detected methods was assessed by utilizing the Human Protein Atlas (HPA). The impact of the selected hub genes on the prognosis of HNSCC patients was assessed by analysing immunohistochemistry (IHC) and immunofluorescence (IF) expression levels and clinical data. Results: Twenty-four genes positively correlated with tumour status and 15 genes negatively correlated with tumour status were screened out by WGCNA. PLAU and LAMC2 were associated with a poor prognosis in patients with HNSCC and were finally screened out and verified by GEPIA and HPA database analysis. Immunohistochemistry of samples collected from 175 patients with HNSCC and subsequent statistical analysis also showed that PLAU and LAMC2 were associated with a poor prognosis in patients with HNSCC, and the levels of these two factors were positively correlated. The expression and co-localization of PLAU and LAMC2 in HNSCC tissues were confirmed by double immunofluorescence labeling. Conclusions: There was a positive correlation between PLAU and LAMC2 expression in HNSCC samples, and PLAU and LAMC2 might be independent prognostic biomarkers for HNSCC.