SOD2- and NRF2-associated Gene Signature to Predict Radioresistance in Head and Neck Cancer.
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ABSTRACT: Background
We propose a novel prognostic biomarker-based strategy for increasing the efficacy of radiotherapy (RT) in head and neck squamous cell carcinoma (HNSCC).Materials and methods
We identified genes associated with superoxide dismutase 2 (SOD2) and nuclear factor erythroid-2-related factor 2 (NRF2) from gene-expression data of The Cancer Genome Atlas (TCGA) by calculating Pearson correlation. Patients were divided into two groups using hierarchical clustering. Colony-formation assay was performed to determine radioresistance in HNSCC cell line CAL27. Pathway analysis was conducted using The Database for Annotation, Visualization and Integrated Discovery (DAVID).Results
We developed a 49-gene signature with SOD2- and NRF2-associated genes. Using mRNA expression data for the 49-gene signature, we performed hierarchical clustering to stratify patients into two subtypes, subtype A and B. In the TCGA cohort, subgroup A demonstrated a better prognosis than subgroup B in patients who received RT. The signature robustness was evaluated in other independent cohorts. We showed through colony-formation assay that depletion of SOD2 or NRF2 leads to increased radiosensitivity.Conclusion
We identified and validated a robust gene signature of SOD2- and NRF2-associated genes in HNSCC and confirmed their link to radioresistance using in vitro assay, providing a novel biomarker for the evaluation of HNSCC prognosis.
SUBMITTER: Noh JK
PROVIDER: S-EPMC8441763 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRadiotherapy is an indispensable treatment modality in head and neck cancer (HNC), while radioresistance is the major cause of treatment failure. The aim of this study is to identify a prognostic molecular signature associated with radio-resistance in HNC for further clinical applications.MethodsAffymetrix cDNA microarrays were used to globally survey different transcriptomes between HNC cell lines and isogenic radioresistant sublines. The KEGG and Partek bioinformatic analytical methods were used to assess functional pathways associated with radioresistance. The SurvExpress web tool was applied to study the clinical association between gene expression profiles and patient survival using The Cancer Genome Atlas (TCGA)-head and neck squamous cell carcinoma (HNSCC) dataset (n = 283). The Kaplan-Meier survival analyses were further validated after retrieving clinical data from the TCGA-HNSCC dataset (n = 502) via the Genomic Data Commons (GDC)-Data-Portal of National Cancer Institute. A panel maker molecule was generated to assess the efficacy of prognostic prediction for radiotherapy in HNC patients.ResultsIn total, the expression of 255 molecules was found to be significantly altered in the radioresistant cell sublines, with 155 molecules up-regulated 100 down-regulated. Four core functional pathways were identified to enrich the up-regulated genes and were significantly associated with a worse prognosis in HNC patients, as the modulation of cellular focal adhesion, the PI3K-Akt signaling pathway, the HIF-1 signaling pathway, and the regulation of stem cell pluripotency. Total of 16 up-regulated genes in the 4 core pathways were defined, and 11 over-expressed molecules showed correlated with poor survival (TCGA-HNSCC dataset, n = 283). Among these, 4 molecules were independently validated as key molecules associated with poor survival in HNC patients receiving radiotherapy (TCGA-HNSCC dataset, n = 502), as IGF1R (p = 0.0454, HR = 1.43), LAMC2 (p = 0.0235, HR = 1.50), ITGB1 (p = 0.0336, HR = 1.46), and IL-6 (p = 0.0033, HR = 1.68). Furthermore, the combined use of these 4 markers product an excellent result to predict worse radiotherapeutic outcome in HNC (p < 0.0001, HR = 2.44).ConclusionsFour core functional pathways and 4 key molecular markers significantly contributed to radioresistance in HNC. These molecular signatures may be used as a predictive biomarker panel, which can be further applied in personalized radiotherapy or as radio-sensitizing targets to treat refractory HNC.
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Project description:PurposeHead and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer globally, and radiotherapy plays a crucial part in its treatment. This study was designed to identify potential genes related to radiation resistance in HNSCC.MethodWe first used text mining to obtain common genes related to radiotherapy resistance and HNSCC in published articles. Functional enrichment analyses were conducted to identify the significantly enriched pathways and genes. Protein and protein interactions were performed, and the most significant gene modules were determined; then, genes in the gene modules were validated at transcriptional levels and overall survival. Gene set variation analysis (GSVA) score was calculated, and the association between GSVA score and survival/pathway was estimated. Immune cell infiltration, methylation, and genetic alteration analysis of these genes was conducted in HNSCC patients. Finally, potential sensitive anticancer drugs related to target genes were obtained.ResultWe identified 583 common genes through text mining. After further validation, a four-gene signature (EPHB2, SPP1, SERPINE1, and VEGFC) was constructed. The patients with higher GSVA scores have a worse prognosis than those with lower GSVA scores. Differences in methylation of these four genes in HNSCC tumor tissue and normal tissue were compared, with higher methylation levels of EBPH2 and SPP1 in normal tissue and higher methylation levels of SERPINE1 in the tumor. Immune cell infiltration revealed that the increased expression of these genes was closely related to the infiltration level of CD4+ T cell, neutrophil, macrophage, and dendritic cell. Thirty drugs, including 22 positively and eight negatively correlated drugs that most correlated with related genes, were available for treating HNSCC.ConclusionIn this study, we identified four potential genes as well as corresponding drugs that might be related to radioresistance in HNSCC patients. These candidate genes may provide a promising avenue to further elevate radiotherapy efficacy.
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Project description:The clinical management of head and neck squamous cell carcinoma (HNSCC) commonly involves chemoradiotherapy, but recurrences often occur that are associated with radioresistance. Using human SQD9 laryngeal squamous cell carcinoma cancer cells as a model, we aimed to identify metabolic changes associated with acquired radioresistance. In a top-down approach, matched radiosensitive and radioresistant SQD9 cells were generated and metabolically compared, focusing on glycolysis, oxidative phosphorylation (OXPHOS) and ROS production. The cell cycle, clonogenicity, tumor growth in mice and DNA damage-repair were assessed. Mitochondrial DNA (mtDNA) was sequenced. In a bottom-up approach, matched glycolytic and oxidative SQD9 cells were generated using FACS-sorting, and tested for their radiosensitivity/radioresistance. We found that acquired radioresistance is associated with a shift from a glycolytic to a more oxidative metabolism in SQD9 cells. The opposite was also true, as the most oxidative fraction isolated from SQD9 wild-type cells was also more radioresistant than the most glycolytic fraction. However, neither reduced hexokinase expression nor OXPHOS were directly responsible for the radioresistant phenotype. Radiosensitive and radioresistant cells had similar proliferation rates and were equally efficient for ATP production. They were equally sensitive to redox stress and had similar DNA damage repair, but radioresistant cells had an increased number of mitochondria and a higher mtDNA content. Thus, an oxidative switch is associated with but is not responsible for acquired radioresistance in human SQD9 cells. In radioresistant cells, more abundant and fitter mitochondria could help to preserve mitochondrial functions upon irradiation.
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Project description:(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy.
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Project description: Not available
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Project description:BackgroundTo parse the characteristics of aneuploidy related riskscore (ARS) model in head and neck squamous cell carcinomas (HNSC) and their predictive ability on patient prognosis.MethodsMolecular subtyping of HNSC specimens was clustered by Copy Number Variation (CNV) data from The Cancer Genome Atlas (TCGA) dataset applying consistent clustering, followed by immune condition evaluation, differentially expressed genes (DEGs) analysis and DEGs function annotation. Weighted gene co-expression network analysis (WGCNA), protein-protein interaction, Univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox regression analysis were implemented to construct an ARS model. A nomogram for clinic practice was designed by rms package. Immunotherapy evaluation and drug sensitivity prediction were also carried out.ResultsWe stratified HNSC patients into three different molecular subgroups, with the best prognosis in C1 cluster among 3 clusters. C1 cluster displayed greatest immune infiltration status. The most DEGs between C1 and C2 groups, mainly enriched in cell cycle and immune function. We constructed a nine-gene ARS model (ICOS, IL21R, CCR7, SELL, CYTIP, ZAP70, CCR4, S1PR4 and CD79A) that effectively differentiates between high- and low-risk patients. Patients in low ARS group showed a higher sensitivity to immunotherapy. A nomogram built by integrating ARS and clinic-pathological characteristics helped predict clinic survival benefit. Drug sensitivity evaluation found that 4/9 inhibitor drugs (MK-8776, AZD5438, PD-0332991, PHA-665752) acted on the cell cycle.ConclusionsWe classified 3 molecular subtypes for HNSC patients and established an ARS prognostic model, which offered a prospective direction for prognosis in HNSC.
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2022-03-16 | GSE195832 | GEO