Prognostic association of starvation-induced gene expression in head and neck cancer.
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ABSTRACT:
SUBMITTER: Hamada M
PROVIDER: S-EPMC8476550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The occurrence and prognosis of head and neck squamous cell cancer (HNSC) is closely associated with human papillomavirus (HPV) infection. Transmembrane channel-like 8 (TMC8) is a key gene affecting the susceptibility of HPV and that plays an important role in T cell regulation. However, the mechanism by which TMC8 affects T cells and whether it further affects the prognosis of patients with HNSC remains unclear. In the present study, oral cancer cell lines and independent tumor specimens were used to detect TMC8 expression in HNSC. Differential expression of TMC8, methylation status, function and associated signaling pathways were further analyzed. Then, multiple databases were cross-analyzed for the relationship of TMC8 with immune cell infiltration and its impact on the prognosis of numerous types of cancer. The results showed that TMC8 was upregulated in HNSC and high expression was predictive of an improved prognosis. Furthermore, TMC8 was concentrated in multiple immune-associated signaling pathways and the expression of TMC8 was associated with the infiltration of CD4+ T cells and their subsets, including CD8+ T cells, B cells and macrophages, suggesting that TMC8 may play an anti-HPV role by regulating CD4+ T cells. Thus, TMC8 plays an anti-HPV role by regulating the infiltration level of CD4+ T cells, and could therefore be used as a potential prognostic marker for patients with HNSC.
| S-EPMC8108259 | biostudies-literature
Project description:In patients with head and neck cancer (HNC), lymph node (N) metastases are associated with cancer aggressiveness and poor prognosis. Identifying meaningful gene modules and representative biomarkers relevant to the N stage helps predict prognosis and reveal mechanisms underlying tumor progression. The present study used a step‑wise approach for weighted gene co‑expression network analysis (WGCNA). Dataset GSE65858 was subjected to WGCNA. RNA sequencing data of HNC downloaded from the Cancer Genome Atlas (TCGA) and dataset GSE39366 were utilized to validate the results. Following data preprocessing, 4,295 genes were screened, and blue and black modules associated with the N stage of HNC were identified. A total of 16 genes [keratinocyte differentiation associated protein, suprabasin, cornifelin (CNFN), small proline rich protein 1B, desmoglein 1 (DSG1), chromosome 10 open reading frame 99, keratin 16 pseudogene 3, gap junction protein β2, dermokine, LY6/PLAUR domain containing 3, transmembrane protein 79, phospholipase A2 group IVE, transglutaminase 5, potassium two pore domain channel subfamily K member 6, involucrin, kallikrein related peptidase 8] that had a negative association with the N‑stage in the blue module, and two genes (structural maintenance of chromosomes 4 and mutS homolog 6) that had a positive association in the black module, were identified to be candidate hub genes. Following further validation in TCGA and dataset GSE65858, it was identified that CNFN and DSG1 were associated with the clinical stage of HNC. Survival analysis of CNFN and DSG1 was subsequently performed. Patients with increased expression of CNFN displayed better survival probability in dataset GSE65858 and TCGA. Therefore, CNFN was selected as the hub gene for further verification in the Gene Expression Profiling Interactive Analysis database. Finally, functional enrichment and gene set enrichment analyses were performed using datasets GSE65858 and GSE39366. Three gene sets, namely 'P53 pathway', 'estrogen response early' and 'estrogen response late', were enriched in the two datasets. In conclusion, CNFN, identified via the WGCNA algorithm, may contribute to the prediction of lymph node metastases and prognosis, probably by regulating the pathways associated with P53, and the early and late estrogen response.
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Project description:BackgroundTumor hypoxia plays a fundamental role in resistance to therapy and disease progression. A number of studies have assessed the prognostic role of HIFs expression in head and neck cancer (HNC), but no consistent outcomes are reported.MethodologyA systematical search was performed to search relevant literatures in PubMed, Web of Science and ISI Web of Knowledge databases. The patients' clinical characteristics and survival outcome were extracted. The correlation between HIFs expression and prognosis was analyzed.Principal findingsA total of 28 studies assessed the association between HIFs and HNC survival, the result showed that overexpressed HIFs was significantly associated with increase of mortality risk (HR = 2.12; 95% CI: 1.52-2.94; I(2) 74%). Subgroup analysis on different HIF isoforms with OS indicated that both HIF-1α and HIF-2α were associated with worse prognosis. The pooled HRs were 1.72(95% CI 1.34-2.20; I(2) 70.7%) and 1.79(95% CI: 1.42-2.27, I(2) 0%). Further subgroup analysis was performed by different geographical locations, disease subtype, stage, types of variate analysis and cut-off value. The results revealed that overexpressed HIF-1α was significantly associated with poor prognosis in Asian patients (HR = 2.34; 95% CI: 1.76-3.1; I(2) 48.9%), but not in European patients (HR = 1.13; 95% CI: 0.77-1.66; I(2) 78.3%). Furthermore, HIF-1α overexpression was significantly associated with worse OS in oral carcinoma (HR = 2.1; 95% CI: 1.11-3.97; I(2) 81.7%), nasopharyngeal carcinoma (HR = 2.07; 95% CI:1.23-3.49; I(2) 22.5%) and oropharynx carcinoma (HR = 1.76; 95% CI:1.05-2.97; I(2) 61%), but not in laryngeal carcinoma (HR = 1.38; 95% CI: 0.87-2.19; I(2) 62.5%). We also found that the prognostic value of HIF-1α overexpression existed only when using staining and percentage as positive definition (HR = 1.82; 95% CI 1.42-2.33; I(2) 9.9%).ConclusionsThis study showed that overexpressed HIFs were significantly associated with increase of mortality risk. Subgroup analysis revealed that overexpressed HIF-1α was significantly associated with worse prognosis of HNC in Asian countries. Additionally, HIF-1α had different prognostic value in different HNC disease subtypes.
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Project description:BackgroundVarious cancer stem cell (CSC) biomarkers and the genes encoding them in head and neck squamous cell carcinoma (HNSCC) have been identified and evaluated. However, the validity of these factors in the prognosis of HNSCC has been questioned and remains unclear. In this study, we examined the clinical significance of CSC biomarker genes in HNSCC, using five publicly available HNSCC cohorts.MethodsTo predict the prognosis of patients with HNSCC, we developed and validated the expression signatures of CSC biomarker genes whose mRNA expression levels correlated with at least one of the four CSC genes (CD44, MET, ALDH1A1, and BMI1).ResultsPatients in The Cancer Genome Atlas (TCGA) HNSCC cohort were classified into CSC gene expression-associated high-risk (CSC-HR; n = 285) and CSC gene expression-associated low-risk (CSC-LR; n = 281) subgroups. The 5-year overall survival and recurrence-free survival rates were significantly lower in the CSC-HR subgroup than in the CSC-LR subgroup (p = 0.04 and 0.02, respectively). The clinical significance of the CSC gene expression signature was validated using four independent cohorts. Analysis using Cox proportional hazards models showed that the CSC gene expression signature was an independent prognostic factor of non-oropharyngeal HNSCC which mostly indicates HPV (-) status. Furthermore, the CSC gene expression signature was associated with the prognosis of HNSCC patients who received radiotherapy.ConclusionThe CSC gene expression signature is associated with the prognosis of HNSCC and may help in personalized treatments for patients with HNSCC, especially in cases with HPV (-) status who were classified in more detail.
| S-EPMC9583594 | biostudies-literature
Project description:Squamous cell carcinoma of the head and neck (SCCHN) is common worldwide and related to several risk factors including smoking, alcohol consumption, poor dentition and human papillomavirus (HPV) infection. Different etiological factors may influence the tumor microenvironment and play a role in dictating response to therapeutics. Here, we sought to investigate whether an early-stage SCCHN-specific prognostic matrisome-derived gene signature could be identified for HPV-negative SCCHN patients (n = 168), by applying a bioinformatics pipeline to the publicly available SCCHN-TCGA dataset. We identified six matrisome-derived genes with high association with prognostic outcomes in SCCHN. A six-gene risk score, the SCCHN TMI (SCCHN-tumor matrisome index: composed of MASP1, EGFL6, SFRP5, SPP1, MMP8 and P4HA1) was constructed and used to stratify patients into risk groups. Using machine learning-based deconvolution methods, we found that the risk groups were characterized by a differing abundance of infiltrating immune cells. This work highlights the key role of immune infiltration cells in the overall survival of patients affected by HPV-negative SCCHN. The identified SCCHN TMI represents a genomic tool that could potentially aid patient stratification and selection for therapy in these patients.
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Project description:Overexpression of the epidermal growth factor (EGF) receptor (EGFR) is associated with enhanced invasion and metastasis in head and neck squamous cell carcinoma (HNSCC). Long Pentraxin PTX3 is involved in immune escape in cancer cells. Here, we identified PTX3 as a promoting factor that mediates EGF-induced HNSCC metastasis. EGF-induced PTX3 transcriptional activation is via the binding of c-Jun to the activator protein (AP)-1 binding site of the PTX3 promoter. PI3K/Akt and NF-?B were essential for the PTX3 activation. EGF-induced PTX3 expression was blocked in c-Jun- and NF-?B-knockdown cells. EGF-mediated PTX3 secretion resulted in the enhancement of cell migration and invasion, and interactions between cancer and endothelial cells. The tail-vein injection animal model revealed that depletion of PTX3 decreased EGF-primed tumor cell metastatic seeding of the lungs. In addition, fibronectin, matrix metalloproteinase-9 (MMP9) and E-cadherin were essential components in EGFR/PTX3-mediated cancer metastasis. In conclusion, PI3K/Akt and NF-?B-dependent regulation of AP-1 mediates PTX3 transcriptional responses to EGF. Autocrine production of EGF-induced PTX3 in turn induces metastatic molecules, activating inflammatory cascades and metastasis.
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Project description:Objectives/hypothesisA reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC).Study designProspective cohort study.MethodsA panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient's serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models.ResultsPoor overall survival was associated with African Americans (hazard ratio [HR] for death = 2.61; 95% confidence interval [CI]: 1.58-4.33; P = .000), advanced stage (HR = 2.79; 95% CI: 1.40-5.57; P = .004), and recurrent disease (HR = 6.66; 95% CI: 2.54-17.44; P = .000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival.ConclusionsThe results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted.
| S-EPMC4129948 | biostudies-literature
Project description:BackgroundHead and neck squamous cell carcinoma (HNSC) ranks as the sixth most common malignancy. The identification of highly specific and sensitive prognostic markers and potential drug targets can contribute to enhanced patient prognosis and individualized treatments. Heat shock proteins (HSPs) act as molecular chaperones and play a crucial role in maintaining cell homeostasis. Recently, research has indicated that HSPs also act as "evil chaperones" in cancer development.MethodsIn this study, we assessed the expression of HSPs in HNSC patients using the ONCOMINE, GEPIA, and UALCAN databases. Mutations of HSP genes were also analysed using the cBioPortal database. Additionally, the expression levels of HSPs were verified using the Human Protein Altas (THPA) database.ResultsWe found that the expression levels of HSPH1, HSPD1, SERPINH1, HSPA4, and HSP90AA1 were significantly higher in tissues from HNSC patients compared with normal tissues. Moreover, HSPH1, HSPD1, SERPINH1, HSPA4 and HSP90AA1 expressions were linked to disease progression. Survival analysis with the GEPIA and OncoLnc databases indicated that upregulation of HSPH1, HSPD1, SERPINH1, HSPA4 and HSP90AA1 was related to poor overall survival (OS).ConclusionThis study suggests that the HSPH1, HSPD1, SERPINH1, HSPA4 and HSP90AA1 genes are potential clinical targets and prognostic biomarkers for patients with HNSC.
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Project description:The tumor microenvironment (TME) is of great clinical significance for predicting the therapeutic effect of tumors. Nonetheless, there was no systematic analysis of cellular interactions in the TME of head and neck cancer (HNSC). This study used gene expression data from 816 patients with HNSC to analyze the scores of 22 immune cells. On this basis, we have established a novel TMEscore-based prognostic risk model. The relationship between TMEscore and clinical and genomic characteristics was analyzed. The sample was divided into risk-H and risk-L groups based on the prognosis risk model of TMEscore, with significant differences in overall survival between the two groups (log rank p < 0.001). In terms of clinical features, the TMEscore is closely related to the T staging, Grade, and HPV. As for genomic characteristics, the genomic features of the Risk-H samples are a low expression of immune-related genes and high-frequency mutations of TP53 and CEP152. This model was validated in an external test set, in which the prognosis for Risk-H group and Risk-L group was also significantly different (log rank p = 0.017). A quantitative method of TME infiltration pattern is established, which may be a potential predictor of HNSC prognosis.
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Project description:Previous studies have shown that high uptake of (18)F-fluoro-2-deoxy-glucose in head and neck cancer, as determined by the standardized uptake value on positron emission tomography scan, was associated with poor survival. The aim of this study was to confirm the association and to establish whether a high standardized uptake value had prognostic significance. Seventy-three consecutive patients with newly diagnosed squamous cell carcinoma of the head and neck underwent a positron emission tomography study before treatment. Age, gender, performance status tumour grade, stage, maximal tumour diameter and standardized uptake value were analyzed for their possible association with survival. The median standardized uptake value for all primary tumours was 7.16 (90% range 2.30 to 18.60). In univariate survival analysis the cumulative survival was decreased as the stage, tumour diameter and standardized uptake value increased. An standardized uptake value of 10 was taken as a cut-off for high and low uptake tumours. When these two groups were compared, an standardized uptake value >10 predicted for significantly worse outcome (P=0.003). Multivariate analysis demonstrated that an standardized uptake value >10 provided prognostic information independent of the tumour stage and diameter (P=0.002). We conclude that high FDG uptake (standardized uptake value>10) on positron emission tomography is an important marker for poor outcome in primary squamous cell carcinoma of the head and neck. Standardized uptake value may be useful in distinguishing those tumours with a more aggressive biological nature and hence identifying patients that require intensive treatment protocols including hyperfractionated radiotherapy and/or chemotherapy.
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