Upregulation of SQLE Contributes to Poor Survival in Head and Neck Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Li J
PROVIDER: S-EPMC9254471 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Quantitative (iTRAQ 4-plex) proteomic analysis of progressive head and neck cancers
2022-03-01 | PXD001438 | Pride
Project description:Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.
| S-EPMC7944998 | biostudies-literature
Project description:(1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and rare immune cell subtypes and survival outcomes in HNSCC. (2) Methods: In this cohort study, we utilized a deconvolution approach based on the CIBERSORT algorithm and the LM22 signature matrix to infer proportions of immune cell subtypes from 517 patients with untreated HPV-negative HNSCC from The Cancer Genome Atlas. We performed univariate and multivariable survival analysis, integrating immune cell proportions with clinical, pathologic, and genomic data. (3) Results: We reliably deconvolved 22 immune cell subtypes in most patients and found that the most common immune cell types were M0 macrophages, M2 macrophages, and memory resting CD4 T cells. In the multivariable analysis, we identified advanced N stage and the presence of γδ T cells as independently predictive of poorer survival. (4) Conclusions: We uncovered that γδ T cells in the tumor microenvironment were a negative predictor of survival among patients with untreated HNSCC. Our findings underscore the need to better understand the role of γδ T cells in HNSCC, including potential pro-tumorigenic mechanisms, and whether their presence may predict the need for alternative therapy approaches.
| S-EPMC10571517 | biostudies-literature
Project description:For TP53-mutated head and neck squamous cell carcinomas (HNSCCs), the codon and specific amino acid sequence change resulting from a patient's mutation can be prognostic. Thus, developing a framework to predict patient survival for specific mutations in TP53 would be valuable. There are many bioinformatics and functional methods for predicting the phenotypic impact of genetic variation, but their overall clinical value remains unclear. Here, we assess the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation, using TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence. These methods include: server-based computational tools SIFT, PolyPhen-2, and Align-GVGD; our in-house POSE and VEST algorithms; the rules devised in Poeta et al. with and without considerations for splice-site mutations; location of mutation in the DNA-bound TP53 protein structure; and a functional assay measuring WAF1 transactivation in TP53-mutated yeast. We assessed method performance using overall survival (OS) and progression-free survival (PFS) from 420 HNSCC patients, of whom 224 had TP53 mutations. Each mutation was categorized as "disruptive" or "non-disruptive". For each method, we compared the outcome between the disruptive group vs. the non-disruptive group. The rules devised by Poeta et al. with or without our splice-site modification were observed to be superior to others. While the differences in OS (disruptive vs. non-disruptive) appear to be marginally significant (Poeta rules + splice rules, P = 0.089; Poeta rules, P = 0.053), both algorithms identified the disruptive group as having significantly worse PFS outcome (Poeta rules + splice rules, P = 0.011; Poeta rules, P = 0.027). In general, prognostic performance was low among assessed methods. Further studies are required to develop and validate methods that can predict functional and clinical significance of TP53 mutations in HNSCC patients.
| S-EPMC4324386 | biostudies-literature
Project description:Background Discoidin domain receptor 2 (DDR2) is a unique receptor tyrosine kinase (RTK) that is activated by fibrillar collagens. Although DDR2 contributes to the metastasis of some tumors, its role in head and neck squamous cell carcinoma (HNSCC) remains unknown. The aim of this study was to investigate the expression level, clinical and pathological significance, and biologic function of DDR2 in HNSCC. Methods Real-time quantitative PCR, western blot, and immunohistochemical staining were employed to assess the expression levels of DDR2 in HNSCC specimens. Adenovirus-mediated overexpression of DDR2 was used to evaluate its consequences on cell proliferation, invasion, migration, and the process of hypoxia-induced epithelial-mesenchymal transition (EMT). Then nude mouse xenograft and tail vein metastasis models were utilized to validate the in vitro results. Results DDR2 was highly expressed in high grade HNSCC tissues and lowly expressed in low grade HNSCC tissues, but absent or rarely expressed in cancer-associated normal tissues. Both the frequency and expression intensity of DDR2 were significantly associated with tumor pathologic stage and lymph node metastasis. In vitro, DDR2 overexpression in HNSCC cells failed to alter cell proliferation but markedly accelerates cell invasion and migration as well as hypoxia-induced EMT. In vivo, elevated expression of DDR2 speeds up the metastasis of HNSCC cells to the lung. Conclusion DDR2 plays an important role in HNSCC metastasis, and might be a promising target for future therapies in this type of cancer.
| S-EPMC4026084 | biostudies-other
Project description:The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck.A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53-DNA complexes. TP53 mutational status was compared with clinical outcome.TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P=0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P<0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P=0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P=0.003).Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.
| S-EPMC2263014 | biostudies-literature
Project description:The squamous cell carcinomas represent about 90 % of all head and neck cancers, ranking the sixth most common human cancer. Approximately 450,000 of new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed every year. Unfortunately, because of diagnosis at the advanced stages and early metastasis to the lymph nodes, the HNSCC is associated with very high death rate. Identification of signature biomarkers and molecularly targeted therapies could provide more effective and specific cancer treatment, prevent recurrence, and increase survival rate. We used paired tumor and adjacent normal tissue samples to screen with RT² Profiler™ PCR Array Human Cancer PathwayFinderTM . Total of 20 up-regulated genes and two down-regulated genes were screened out. Out of 22 genes, 12 genes were subsequently validated to be significantly altered in the HNSCC; the samples were from all 41 patients. Five year survival and recurrence selected genes that could represent the biomarkers of survival and recurrence of the disease. We believe that comprehensive understanding of the unique genetic characteristics of HNSCC could provide novel diagnostic biomarkers and meet the requirement for molecular-targeted therapy for the HNSCC.
| S-EPMC4381614 | biostudies-literature
Project description:BackgroundDCBLD1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the prognostic value and immune infiltration in head and neck squamous cell carcinoma remain unclear and need further research.Materials and methodsDCBLD1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. The mRNA level in cell lines (SCC25 and CAL27) and gingival fibroblasts were detected using quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of DCBLD1 and clinical data in HNSCC. A nomogram was also established to predict the impact of DCBLD1 on prognosis based on Cox multivariate results. The methylation level of DCBLD1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of DCBLD1 were investigated using gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA).ResultsThe mRNA and protein expression levels of DCBLD1 were highly expressed in HNSCC tissue and cell lines. The Cox analyses demonstrate that highly expressed DCBLD1 is an independent prognosis marker (p < 0.05). ROC curve analysis showed the performance of DCBLD1 (area under the ROC curve: 0.948, sensitivity: 93.2%, specificity: 84.7%). The methylation was increased in HNSCC patients compared with normal subjects (p < 0.05) and was associated with poor prognosis at sites cg27642470 and cg21104965. Additionally, DCBLD1 expression is poorly associated with immune cell infiltration and immunological checkpoints PD-L1 and TIM-3.ConclusionIn head and neck squamous cell carcinoma, DCBLD1 is overexpressed, associated with poor patient prognosis. The detailed underlying mechanism merits further research.
| S-EPMC9283650 | biostudies-literature
Project description:Hypoxanthine phosphoribosyltransferase (HPRT1), as a salvage pathway enzyme, plays a crucial role in modulating the cell cycle and has been reported to be overexpressed in multiple cancers. Nevertheless, the relationship between the HPRT1 gene and head and neck squamous cell carcinomas (HNSCCs) has not been investigated so far. In this study, we first evaluated the expression and clinical value of HPRT1 mRNA and protein in tumor and healthy control tissues. Then, we examined mutations of the HPRT1 gene and their association with survival outcomes of patients with HNSCC. We also performed functional analyses of HPRT1 coexpressed genes and examined the association between HPRT1 expression and drug sensitivity. Both HPRT1 mRNA and protein were significantly higher in HNSCC compared with normal tissues, and up-regulation of HPRT1 was also correlated with age, sex, pathological stage and histological grades of patients with HNSCC. Moreover, HPRT1 and its associated genes were observed to be enriched for several cancer-related pathways, including DNA replication and cell cycle. Finally, patients exhibiting overexpression of the HPRT1 gene may be resistant to abiraterone and sensitive to several drugs, including tozasertib and teniposide. This study demonstrated that the elevated expression of HPRT1 gene is correlated with the progression of HNSCC; thus, this gene may serve as a useful indicator for the early detection, risk stratification and targeted therapy of patients with HNSCC.
| S-EPMC8409317 | biostudies-literature
Project description:Regional lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) is a crucial event for its progression, associated with a high rate of mortality. Sialidase, a key enzyme for the regulation of cellular sialic acids through catalyzing the initial step of degradation of glycoproteins and glycolipids, has been implicated in cancer progression. To facilitate the development of novel treatments for HNSCC, we have investigated whether sialidase is involved in the progression of this cancer. We found plasma membrane-associated sialidase (NEU3) to be significantly upregulated in tumor compared to non-tumor tissues; particularly, an increase in its mRNA levels was significantly associated with lymph node metastasis. To understand the mechanisms, we analyzed the NEU3-mediated effects on the malignant phenotype using squamous carcinoma HSC-2 and SAS cells. NEU3 promoted cell motility and invasion, accompanied by the increased expression of MMP-9, whereas NEU3 silencing or the activity-null mutant did not. NEU3 enhanced phosphorylation of epidermal growth factor receptor (EGFR), and an EGFR inhibitor, AG1478, abrogated the NEU3-induced MMP9 augmentation. These findings identify NEU3 as a participant in HNSCC progression through the regulation of EGFR signaling and thus as a potential target for inhibiting EGFR-mediated tumor progression.
| S-EPMC4714679 | biostudies-literature