Biomarkers For Head And Neck Squamous Cell Carcinoma Research Articles

Aberrant promoter methylation of CTHRC1 gene and its clinicopathological characteristics in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is genetically complex and difficult to treat. Detection in the early stage is challenging, leading to diagnosis at advanced stages with limited treatment options. This study examined the collagen triple helix repeat containing 1 gene (CTHRC1) as a potential biomarker and therapeutic target in HNSCC. Despite documented CTHRC1 upregulation in various cancers, the underlying causes remain unclear. The objective was to investigate potential epigenetic regulation of CTHRC1 expression through the analysis of promoter methylation. CTHRC1 DNA methylation, mRNA, and its protein expression were analysed using The Cancer Genome Atlas (TCGA) HNSCC cohort and oral squamous cell carcinoma (OSCC) patient samples. Functional analysis included scrutinizing the protein-protein interaction network and associations with DisGeNET (disease gene network). Various statistical methods were employed for analysis. HNSCC tumours exhibited significant hypomethylation of CTHRC1 DNA, correlating with advanced disease features. Elevated mRNA and protein expression of CTHRC1 further support its role in disease progression. High CTHRC1 gene expression was associated with a poorer prognosis. The protein interaction network implicated crucial pathways in cancer development and links to oral submucous fibrosis. Despite the limitations of this study, including the use of retrospective data and need for functional experiments, CTHRC1 shows potential as a prognostic predictor and target for therapeutic applications in HNSCC, paving the way for further research and improved patient management.

Overexpressed RPS6KA1 and its potential diagnostic value in head and neck squamous cell carcinoma

RPS6KA1 express disorder is associated with many cancers, but the role in head and neck squamous cell carcinoma (HNSCC) and the specific mechanism is still unclear. We used bioinformatics analysis to explore the role of Ribosomal Protein S6 Kinase A1(RPS6KA1) in HNSCC which were predicted to regulate certain pathway and immune microenvironment to increase the risk in HNSCC. Multiple bioinformatics tools based on the EBI, GEO, TCGA databases and clinical samples were used to analyze the expression of RPS6K1 in HNSCC. Western blot (WB) and PCR results confirmed the upregulation of RPS6KA1 in HNSCC tissues. Flow cytometry was used to validate the relationship between RPS6KA1 and immune cell infiltration in the tumor microenvironment. The correlation of RPS6KA1 with the immune environment was further analyzed, and flow cytometry validation was performed in HNSCC samples. Then, Gene Ontology(GO) and Gene Set Enrichment Analysis(GSEA) analysis were used to explore the pathway which could be regulated by RPS6KA1 in HNSCC. And drug sensitivity analysis was used to the access the relationships between RPS6KA1 and drugs therapeutic effects. EBI, TCGA and GEO databases were used to reveal that RPS6KA1 expression was significantly increased in HNSCC, especially in III + IV HNSCC. And it was related to many types of immune cells and immune adjustment factors and positively correlated with tumor immune score and B cells, but had no significant correlation with CD4+ and CD8+ T cells. Drug sensitivity analysis revealed that RPS6KA1 has certain predictive value. In this research, we indicated that RPS6KA1 is overexpressed and may serve as a potential diagnostic and therapeutic biomarker in HNSCC.

MiR-15a-5p Knockdown up-Regulated ABCB1 Expression and Abated HNSCC Progression via the NF-κB Signaling Pathway

Background The high invasion and heterogeneity of head and neck squamous cell carcinoma (HNSCC) commonly leads to poor clinical outcomes. Identification of reliable biomarkers for HNSCC is imperative. Methods The targeted gene with the highest mutation was screened out in cBioPortal database, and the interactive microRNAs (miRNAs) were identified by miRNA-mRNA co-expression analysis. CCK-8 and transwell assays were used to explore the proliferative, migrative, and invasive behaviors of HNSCC cells. The dual-luciferase reporter assay and cell transfection experiment were conducted. The role of miR-15a-5p was investigated in the in vivo xenograft mouse model. Results ATP binding cassette transporter 1 (ABCB1) had the highest mutation frequency and multiple mutation types in HNSCC, and the decreased ABCB1 was significantly related to better prognosis of HNSCC patients. MiR-15a-5p was a regulator for ABCB1, which was up-regulated after miR-15a-5p inhibition in vitro. Furthermore, the miR-15a-5p knockdown significantly suppressed HNSCC cell proliferation, migration, and invasion in vitro, and reduced the HNSCC tumor growth and migration capabilities in vivo, possibly through NF-κB signaling pathway. Conclusion Collectively, miR-15a-5p knockdown increased the ABCB1 level and abated the HNSCC progression via the NF-κB signaling pathway. ABCB1 and miR-15a-5p were underlying predictors for HNSCC therapeutic biomarkers.

Dynamic Changes in Circulating Tumor DNA During Immunotherapy for Head and Neck Cancer: SHIZUKU-HN Study.

Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations. Tumor volumes were quantified using 3D reconstruction of CT scans, and data from Japan's C-CAT database (n = 2255) provided insights into ctDNA testing in HNSCC. C-CAT data showed that ctDNA testing was underutilized, performed in only 7% of head and neck cancer cases. In SHIZUKU-HN, mean VAF significantly correlated with tumor volume (Spearman's ρ = 0.70, p = 0.001), often preceding radiographic progression. BRAF and APC mutations disappeared in partial responders, while GNAS mutations varied. EGFR and PIK3CA amplifications, detectable via ctDNA but missed in tissue biopsies, indicated emerging resistance mechanisms. The SHIZUKU-HN study demonstrates the potential of ctDNA as a dynamic biomarker in HNSCC, offering early insights into treatment efficacy and informing personalized ICI therapy.

CircRNA_036186 mediates HNSCC progression by regulating 14-3-3ζ.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal malignancy, accounting for 95% of head and neck cancers. Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activating protein ZETA (14-3-3ζ) is central to various signalling pathways and is pivotal in tumour progression. Cancerous and corresponding non-cancerous tissue samples were collected from five patients diagnosed with HNSCC. circRNA and mRNA expression profiles were analyzed using high-throughput sequencing techniques. Potential circRNA-microRNA (miRNA)-mRNA interactions were predicted using bioinformatics tools. The study found that CircRNA_036186 regulates the expression of 14-3-3ζ in HNSCC through miR-193b-5p. These findings suggest that CircRNA_036186 has the potential to be a biomarker and therapeutic target for HNSCC and provide some theoretical basis for further research on the role of circRNA in HNSCC.

Issue Information

COVER: He et al. found that hypoxia and radiotherapy can reverse the promoting effect of cancer‐associated fibroblasts (CAFs) on the migration and invasion of head and neck squamous cell carcinoma (HNSCC), which may weaken the inhibitory effect of ENDOU expression in HNSCC by reducing the delivery of miR‐23b‐5p via CAF‐derived extracellular vesicles. This discovery provides new insights into the role of stromal components in tumor regulation and suggests that ENDOU could serve as a biomarker for HNSCC. See pages 275–289 by for details.

Hypoxia combined with radiation reverses migration and invasion of head and neck squamous cell carcinoma by remodeling extracellular vesicle‐mediated transfer of miR‐23b‐5p from cancer‐associated fibroblasts

AbstractBackgroundCancer‐associated fibroblasts (CAFs), the main matrix components in the tumor microenvironment (TME), play a crucial role in tumor progression. Extracellular vesicles (EVs) as main mediators in intercellular communication can be regulated by hypoxia or radiation.MethodsCAFs were extracted from head and neck squamous cell carcinoma (HNSCC) tissues and CAF‐derived EVs were collected by ultracentrifugation. Bioinformatics analysis determined the role of poly (U)‐specific endonuclease (ENDOU) on HNSCC progression and confirmed that ENDOU inhibited HNSCC progression by overexpressing ENDOU in HNSCC. Dual‐luciferase activity report assay confirmed that miR‐23b‐5p was involved in the regulation of ENDOU expression. The migration and invasion of HNSCC cells were verified by transwell assay. Furthermore, tumor‐bearing mouse models were used to demonstrate the potential of EVs loaded with miR‐23b‐5p in HNSCC to promote tumor progression.ResultsOur results showed that ENDOU was downregulated in HNSCC and inhibited HNSCC migration and invasion. Hypoxia and radiotherapy reversed CAF‐derived EVs to promote migration and invasion of HNSCC. Mechanically, hypoxia and radiation downregulated miR‐23b‐5p in CAF‐derived EVs and then restored ENDOU expression in HNSCC. Finally, CAF‐derived EVs carrying miR‐23b‐5p promoted the progression of HNSCC cells in vivo by regulating ENDOU expression.ConclusionThis study demonstrated that hypoxia combined with radiation reverses the promoting effect of CAFs on HNSCC migration and invasion by reducing the delivery of miR‐23b‐5p by CAF‐derived EVs to decrease the inhibitory effect of ENDOU expression in HNSCC. The results provide a new perspective for better understanding the role of stromal components in TME in tumor regulation. Furthermore, the results provide a strong basis for the possibility of ENDOU as a biomarker for HNSCC.

SAR1A Induces Cell Growth and Epithelial-Mesenchymal Transition Through the PI3K/AKT/mTOR Pathway in Head and Neck Squamous Cell Carcinoma: An In Vitro and In Vivo Study.

Head and neck squamous cell carcinoma (HNSCC) ranks sixth globally, with a 50% five-year survival rate. SAR1A exhibits high expression levels in various tumor types, yet its specific role in HNSCC remains to be clarified. In vitro assays, such as CCK8, EdU, colony formation, wound-healing, transwell, and Western blotting analyses, as well as in vivo assays, such as tumor xenografts and lung metastasis models, were conducted to evaluate the impacts of SAR1A on HNSCC proliferation, migration, and invasion. Transcriptome sequencing and KEGG enrichment pathway analysis revealed evident alterations in the PI3K/AKT/mTOR(PAM) pathways. LY294002 (a PI3K/AKT inhibitor) was used to investigate the role of the PAM pathway in proliferation, migration, and invasion in HNSCC. Univariate and multivariate Cox regression were conducted to screen SAR1A as a gene prognostic biomarker in HNSCC, and it was validated in the Cancer Genome Atlas (TCGA) database. Functional assays demonstrated that the depletion of SAR1A leads to suppressed proliferation, migration, and invasion of HNSCC cells. This is accompanied by a decrease in the expression of epithelial-mesenchymal transition (EMT)-related markers in HNSCC cell lines. In addition, the diminished capacities of proliferation, migration, and invasion observed in SAR1A knockdown cells were reversed upon the overexpression of SAR1A. Furthermore, RNA-seq and KEGG enrichment analysis demonstrated a significant alteration in the PAM pathway following SAR1A knockdown. LY294002 effectively mitigated the increased proliferation, migration, and invasion induced by SAR1A overexpression. SAR1A facilitates HNSCC proliferation and EMT via the PI3K/AKT/mTOR pathway.

Plasmonics-enhanced spikey nanorattle-based biosensor for direct SERS detection of mRNA cancer biomarkers.

We present a plasmonics-enhanced spikey nanorattle-based biosensor for direct surface-enhanced Raman scattering (SERS) detection of mRNA cancer biomarkers. Early detection of cancers such as head and neck squamous cell carcinoma (HNSCC) is critical for improving patient outcomes in regions with limited access totraditional diagnostic methods. Our method targets Keratin 14 (KRT14), a promising diagnostic mRNA biomarker for HNSCC, using a sandwich hybridization approach with magnetic beads and SERS spikey nanorattles (SpNR). We synthesized SpNR with a core-gap-shell structure to enhance SERS signals, achieving a limit of detection of 90 femtomolar. A pilot study using clinical samples demonstrated the efficacy of our biosensor in distinguishing between tissue with positive or negative diagnosis for HNSCC, highlighting its potential for rapid and sensitive cancer diagnostics in low-resource settings. This plasmonic assay offers a promising avenue for portable and high-specificity detection of nucleic acid biomarkers, with implications for early cancer detection and improved patient care, especially in middle and low-resource settings.

Super-Enhancer Driven LIF/LIFR-STAT3-SOX2 Regulatory Feedback Loop Promotes Cancer Stemness in Head and Neck Squamous Cell Carcinoma.

Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identify leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine/paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruit SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activates downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlate with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma dramatically diminish following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impairs tumor growth and reduces CSC subpopulations in xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel noninvasive biomarker and potential therapeutic target for HNSCC.

The Next Chapter in Cancer Diagnostics: Advances in HPV-Positive Head and Neck Cancer.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), is an increasingly prevalent pathology worldwide, especially in developed countries. For diagnosing HPV in HNSCC, the combination of p16 immunohistochemistry (IHC) and polymerase chain reaction (PCR) offers high sensitivity and specificity, with p16 IHC being a reliable initial screen and PCR confirming HPV presence. Advanced techniques like next-generation sequencing (NGS) and RNA-based assays provide detailed insights but are primarily used in research settings. Regardless of HPV status, standard oncological treatments currently include surgery, radiation, and/or chemotherapy. This conventional approach does not account for the typically better prognosis of HPV-positive HNSCC patients, leading to increased chemo/radiation-induced secondary morbidities and reduced quality of life. Therefore, it is crucial to identify and detect HPV positivity and other molecular characteristics of HNSCC to personalize treatment strategies. This comprehensive review aims to summarize current knowledge on various HPV detection techniques and evaluate their advantages and disadvantages, with a focus on developing methodologies to identify new biomarkers in HPV-positive HNSCC. The review discusses direct and indirect HPV examination in tumor tissue, DNA- and RNA-based detection techniques, protein-based markers, liquid biopsy potentials, immune-related markers, epigenetic markers, novel biomarkers, and emerging technologies, providing an overall insight into the current state of knowledge.

P4HA3 promotes head and neck squamous cell carcinoma progression via the WNT/β-catenin signaling pathway

Here, we explored the role of Prolyl 4-Hydroxylase Subunit Alpha 3 (P4HA3), the most recently identified member of the prolyl-4-hydroxylase (P4H) family, in head and neck squamous cell carcinoma (HNSCC) progression. P4HA3 is upregulated during cancer progression; however, its specific role in HNSCC progression remains elusive. Thus, this study aimed to elucidate the regulatory function of P4HA3 in HNSCC development and progression and to describe the underlying mechanisms. Initially, we analyzed the correlation between the expression of P4HA3 and the WNT pathway genes and clinicopathologic features in HNSCC based on microarray data from The Cancer Genome Atlas (TCGA). Next, we used Gene Oncology (GO) functional data to describe several potentially associated pathways in HNSCC. Then, we knocked down P4HA3 in SCC15 and SCC25 cells, two classic HNSCC cell lines, and assessed the resulting changes using RT-qPCR. Furthermore, we used Western blot to evaluate the regulatory role of P4HA3 in the epithelial-to-mesenchymal transition (EMT) and the WNT/β-catenin signaling pathway. To explore the effect of P4HA3 knockdown on tumor progression, in vivo experiments were conducted using a murine model. Immunohistochemistry assays were then employed to identify proteins associated with EMT and the WNT/β-catenin signaling pathway in tumor tissues. Upregulated P4HA3 in HNSCC patient tumor tissues was positively correlated with poor prognosis. Notably, P4HA3 knockdown significantly inhibited the proliferative and invasive abilities of HNSCC. The levels of genes and proteins associated with EMT and the WNT/β-catenin signaling pathway were also markedly reduced by P4HA3 knockdown. Importantly, the in vivo experiments demonstrated that P4HA3 can promote subcutaneous tumorigenesis in nude mice and knockdown of P4HA3 induce a significant ihibitation of EMT and WNT/β-catenin pathway detected by immunohistochemistry assay in tumor tissues. In summary, we demonstrated that P4HA3 is a promising diagnostic and therapeutic biomarker for HNSCC. As an oncogene, P4HA3 increases HNSCC proliferation by inducing the EMT and activating the WNT/β-catenin signaling pathway.

Significance of p16 in Site-Specific Human Papillomavirus-Positive and Negative Head and Neck Squamous Cell Carcinoma (HNSCC).

Head and neck squamous cell carcinoma (HNSCC) represents a group of cancers characterized by diverse origins and changing epidemiological patterns. The significance of high-risk human papillomavirus (HPV) infection in certain HNSCC cases has gained attention for its impact on the disease's behavior. Our current research focused on exploring the importance of using p16 as an HNSCC biomarker, particularly in the context of HPV infection, assessing its value in prognosis, and examining its variation across different tumor locations. A retrospective analysis was carried out on 100 HNSCC patients from a tertiary care center, with particular attention paid to p16 expression, HPV status, clinic-pathological characteristics, and prognosis. HPV was detected using polymerase chain reaction (PCR) techniques, and p16 expression was evaluated by immunohistochemistry. According to the ethical guidelines outlined in the Declaration of Helsinki, multivariate analysis assessed the prognostic value of p16. Our analysis demonstrated a significant correlation between HPV status and p16 expression in HNSCC cases. A vast majority of 58 (96.7%) HPV-+cases exhibited p16 overexpression, contrasting sharply with only two (5%) in the HPV--group. Patients with tumors that were both p16+and HPV+exhibited more favorable overall survival rates. In contrast, those with p16-and HPV-tumors experienced the poorest survival outcomes. Notably, having a p16--status in HPV+cases emerged as an independent factor for reduced survival. Additionally, the study revealed distinct variations in p16 expression based on tumor location, particularly within the oropharyngeal area. The study established that p16 is a dependable indication for the existence of HPV in HNSCC and highlights its significant role as a prognostic factor, particularly in cases that are p16--yet HPV-+. These findings underscore the importance of adopting site-specific treatment approaches in HNSCC management and contribute to a deeper understanding of p16's role in the disease, thereby aiding in more effective risk assessment and treatment planning.

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.

The association between the expression level of nuclear paraspeckle assembly transcript 1 and the survival rate of head and neck cancer patients after treatment

Background/purposeThe long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) exhibits diverse and complicated functions in cancer progression. Despite reports suggesting both tumor-suppressive and oncogenic effects in various cancers, its specific role in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study aimed to investigate the association between NEAT1 expression levels and survival outcomes in HNSCC patients. Materials and methodsPaired tissue samples of tumor and non-cancerous matching tissues (NCMT) from 92 HNSCC patients were collected. NEAT1 expression was analyzed using RT-qPCR. Clinical characteristics, treatment received, and survival rates of the patients were assessed to determine the correlation with NEAT1 expression and explore its association with alcohol, betel quid, and cigarette use. Additionally, we examined the effect of arecoline on NEAT1 expression in normal human oral keratinocytes (NHOK) and fibroblasts (NHOF). ResultsThe study revealed a significant downregulation of NEAT1 expression in oral cancer tissues compared to NCMT. Meanwhile, arecoline increased NEAT1 expression in NHOK and NHOF cells. However, patients with downregulated NEAT1 expression exhibited higher overall survival rates, particularly in those who did not receive chemotherapy or radiotherapy. ConclusionNEAT1 expression levels are associated with survival outcomes in HNSCC patients, with upregulated expression indicating a worse prognosis, suggesting this lncRNA might contribute to cancer aggressiveness, especially in the absence of active treatment. These findings indicate NEAT1 may serve as a potential prognostic biomarker in HNSCC, but further research is required to elucidate its role in cancer progression and its potential as a therapeutic target.

Identification of PANoptosis-related biomarkers and analysis of prognostic values in head and neck squamous cell carcinoma

PANoptosis plays a crucial role in cancer initiation and progression. However, the roles of PANoptosis-related genes (PARGs) in the prognosis and immune landscape of head and neck squamous cell carcinoma (HNSCC) remain unclear. Integrated bioinformatics analyses based on the data of HNSCC patients in the TCGA database were conducted. We extracted 48 PARGs expression profile and then conducted differentially expressed analysis, following building a Cox model to predict the survival of HNSCC patients. Subsequently, the relationships between the risk score, immune landscape, chemo-, and immune-therapy responses were analyzed, respectively. Moreover, we investigated the prognostic value, and further predicted the pathways influenced by PARGs. Finally, we identified the biological function of crucial PARGs. A total of 18 differentially expressed PARGs were identified in HNSCC, and a Cox model including CASP8, FADD, NLRP1, TNF, and ZBP1 was constructed, which showed that the risk score was associated with the prognosis as well as immune infiltration of HNSCC patients, and the risk score could be regarded as an independent biomarker. Additionally, patients with high-risk score might be an indicator of lymph node metastasis and advanced clinical stage. High-risk scores also contributed to the chemotherapy resistance and immune escape of HNSCC patients. In addition, FADD and ZBP1 played a crucial role in various cancer-related pathways, such as the MAPK, WNT, and MTOR signaling pathways. On the other hand, we suggested that FADD facilitated the progression and 5-fluorouracil (5-FU) resistance of HNSCC cells. A signature based on PANoptosis showed great predictive power for lymph node metastasis and advanced stage, suggesting that the risk score might be an independent prognostic biomarker for HNSCC. Meanwhile, FADD, identified as a prognostic biomarker, may represent an effective therapeutic target for HNSCC.

Multi-omic analysis and validation reveal ZBP1 as a potential prognostic and immunotherapy-related biomarker in head and neck squamous cell carcinoma

BackgroundPatients with head and neck squamous cell carcinoma (HNSCC) exhibit unfavorable clinical outcomes, accompanied by high morbidity/mortality. In recent years, the management of HNSCC has encountered a significant obstacle. Z-DNA binding protein 1 (ZBP1) exerts crucial biological functions in chronic inflammatory disease and cancer. The aim of this research was to identify the possible function of ZBP1 in HNSCC. MethodsThe Cancer Genome Atlas (TCGA) database was used to collect the gene expression profile and corresponding clinical data. The gene expression, clinical prognosis, genetic alteration, immune characteristics, and subgroup analyses were performed. Meanwhile, an independent cohort (consisting of 66 tumor samples and 37 controls) was employed to validate the expression of ZBP1. ResultsComparing to the normal controls, ZBP1 was upregulated in tumor samples. Low ZBP1 expression predicted undesirable clinical outcomes of HNSCC patients based on the survival analysis. Furthermore, the somatic mutations increased in low ZBP1 expression group. Immune characteristics analysis indicated a positive correlation of ZBP1 expression with the infiltration of immune cells, the expression of immunoregulatory genes and immune checkpoints. In the meantime, single-cell transcriptome analysis unveiled the expression of ZBP1 in tumor microenvironment (TME). In addition, differential gene expression analysis revealed that the expression of ZBP1 primarily contributes to the activation of T cells. Ultimately, ZBP1-associated prognostic and immune features in different subgroups of HNSCC patients were further investigated according to the subgroup analysis. ConclusionOur study comprehensively disclosed that ZBP1 may have the potential to become a meaningful prognostic and immunotherapy-related biomarker for HNSCC.

Identification of AURKA as a Biomarker Associated with Cuproptosis and Ferroptosis in HNSCC.

Cuproptosis and ferroptosis represent copper- and iron-dependent forms of cell death, respectively, and both are known to play pivotal roles in head and neck squamous cell carcinoma (HNSCC). However, few studies have explored the prognostic signatures related to cuproptosis and ferroptosis in HNSCC. Our objective was to construct a prognostic model based on genes associated with cuproptosis and ferroptosis. We randomly assigned 502 HSNCC samples from The Cancer Genome Atlas (TCGA) into training and testing sets. Pearson correlation analysis was utilized to identify cuproptosis-associated ferroptosis genes in the training set. Cox proportional hazards (COX) regression and least absolute shrinkage operator (LASSO) were employed to construct the prognostic model. The performance of the prognostic model was internally validated using single-factor COX regression, multifactor COX regression, Kaplan-Meier analysis, principal component analysis (PCA), and receiver operating curve (ROC) analysis. Additionally, we obtained 97 samples from the Gene Expression Omnibus (GEO) database for external validation. The constructed model, based on 12 cuproptosis-associated ferroptosis genes, proved to be an independent predictor of HNSCC prognosis. Among these genes, the increased expression of aurora kinase A (AURKA) has been implicated in various cancers. To further investigate, we employed small interfering RNAs (siRNAs) to knock down AURKA expression and conducted functional experiments. The results demonstrated that AURKA knockdown significantly inhibited the proliferation and migration of HNSCC cells (Cal27 and CNE2). Therefore, AURKA may serve as a potential biomarker in HNSCC.

Investigating diagnostic potential of long non-coding RNAs in head and neck squamous cell carcinoma using TCGA database and clinical specimens

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and prognostically challenging cancer worldwide. The role of long non-coding RNAs (lncRNAs) in cancer regulation is progressively being understood. This study aims to identify lncRNAs with diagnostic potential as biomarkers for HNSCC. Statistical analysis was performed on expression data from the Cancer Genome Atlas (TCGA) database to identify potential lncRNAs associated with HNSCC. Four selected lncRNAs were validated using real-time quantitative reverse transcription polymerase chain reaction and correlated with clinical factors. Functional roles were further investigated. A total of 488 differentially expressed lncRNAs were identified in TCGA-HNSC. After rigorous evaluation based on p-values, survival analysis, and ROC analysis, 24 lncRNAs were prioritized for additional investigation. LINC00460, LINC00941, CTC-241F20.4, and RP11-357H14.17 were established as candidate diagnostic biomarkers. These lncRNAs exhibited elevated expression in HNSCC tissues and were associated with poor prognosis. Combining them showed high diagnostic accuracy. Notably, LINC00460 and CTC-241F20.4 demonstrated a significant elevation in the advanced stages of HNSCC. We constructed an lncRNA-mRNA regulatory network, and the array of significant regulatory pathways identified included focal adhesion, regulation of epithelial cell migration, and others. Additionally, these lncRNAs were found to influence immune responses by modulating immune cell infiltration in the HNSCC microenvironment. Our research indicates that LINC00460, LINC00941, RP11-357H14.17, and CTC-241F20.4 may have diagnostic and prognostic importance in HNSCC. Furthermore, we have gained insights into their potential functional roles, particularly about immune responses and interactions in the microenvironment.

Hypoxia-induced miR-5100 promotes exosome-mediated activation of cancer-associated fibroblasts and metastasis of head and neck squamous cell carcinoma

The invasion-metastasis cascade in head and neck squamous cell carcinoma (HNSCC) is predominantly caused by the interaction between tumor cells and tumor microenvironment, including hypoxia as well as stromal cells. However, the mechanism of hypoxia-activated tumor-stroma crosstalk in HNSCC metastasis remains to be deciphered. Here, we demonstrated that HIF1α was upregulated in HNSCC specimens compared with adjacent normal tissues, whose overexpression was associated with lymph node metastasis and predicted unfavorable prognosis. HIF1α expression correlated positively with the levels of miR-5100 as well as α-SMA, the marker of CAFs. Hypoxia/HIF1α regulated transcriptionally miR-5100 to promote the degradation of its target gene QKI, which acts as a tumor suppressor in HNSCC. Hypoxic HNSCC-derived exosomal miR-5100 promoted the activation of CAFs by orchestrating QKI/AKT/STAT3 axis, which further facilitated HNSCC metastasis. Additionally, miR-5100 derived from plasma exosomes indicated HNSCC malignant progression. In conclusion, our findings illuminate a novel HIF1α/miR-5100/QKI pathway in HNSCC metastasis, and suggest that miR-5100 might be a potential biomarker and therapeutic target for HNSCC.