MTDH enhances radiosensitivity of head and neck squamous cell carcinoma by promoting ferroptosis based on a prognostic signature.

Ionizing radiation (IR) induces ferroptosis in head and neck squamous cell carcinoma (HNSCC). But, it remains unclear whether ferroptosis affects the prognosis of HNSCC patients after receiving radiotherapy. This study aims to develop a ferroptosis signature to predict the radiosensitivity and prognosis of HNSCC. Ferroptosis-related genes, clinical data and RNA expression profiles were obtained from the FerrDb database, The Cancer Genome Atlas and GEO database. Prognostic genes were identified by random survival forest, univariate Cox regression, Kaplan-Meier and ROC analyses. Principal component analysis, multivariate Cox regression, nomogram and DCA analyses were conducted to estimate its predictive ability. Functional enrichment and immune-related analyses were performed to explore potential biological mechanisms and tumor immune microenvironment. The effect of the hub gene on ferroptosis and radiosensitivity was verified using flow cytometry, quantitative real-time PCR and clonogenic survival assay. We constructed a ferroptosis-related signature, including IL6, NCF2, metadherin (MTDH) and CBS. We classified patients into high-risk (HRisk) and low-risk groups according to the risk scores. The risk score was confirmed to be an independent predictor for overall survival (OS). Combining the clinical stage with the risk score, we established a predictive nomogram for OS. Furthermore, pathways related to tumorigenesis and tumor immune suppression were mainly enriched in HRisk. MTDH was verified to have a potent effect on IR-induced ferroptosis and consequently promoted radiosensitivity. We constructed a ferroptosis-related signature to predict radiosensitivity and OS in HNSCC patients. MTDH was identified as a promising therapeutic target in radioresistant HNSCC patients.

Cao X ，Ge Y ，Yan Z ，Hu X ，Peng F ，Zhang Y ，He X ，Zong D ... -  《-》

Development and validation of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in head and neck squamous cell carcinoma.

Ferroptosis plays an important role across variable cancer types. However, few studies have focused on the prognostic patterns of ferroptosis-related genes in HNSCC. Cohorts with mRNA expression profiles, as well as corresponding clinical data of HNSCC patients from published studies, were collected and consolidated from public databases. We performed random survival forest analysis, Kaplan-Meier (KM) analysis of best combinations, and Cox regression analysis on 231 ferroptosis-related genes to construct a gene signature in the discovery cohort (TCGA), and later validated it in the validation cohort (GEO). The 7-gene signature was constructed to stratify patients into two groups according to their level of risk. Poorer overall survival (OS) was detected in the high risk (HRisk) group than in the low risk (LRisk) group in both the TCGA cohort (P < 0.0001, HR = 1.71, 95%CI:1.41-2.07) and the GEO cohort (P < 0.001, HR = 1.68, 95%CI:1.32-2.13). The risk score was identified as an independent predictive factor of OS in multivariate Cox regression analyses (HR > 1, P < 0.0001) in both cohorts. The signature's predictive capacity was proven by the time-dependent receiver operating characteristic (ROC) curve analysis and nomogram analysis. Functional enrichment analysis revealed that immunosuppressive pathways such as matrix extracellular space, and (transforming growth factor-β)TGF-β were enriched. The HRisk group was strongly associated with upregulation of both cancer-related pathways and stromal scores, while higher proportions of anti-tumor immune cells and immune signatures were enriched in the LRisk group. In conclusion, the signature based on 7 ferroptosis-related genes could be applicable for predicting the prognosis of HNSCC, indicating that ferroptosis may be a potential therapeutic target for HNSCC.

He F ，Chen Z ，Deng W ，Zhan T ，Huang X ，Zheng Y ，Yang H ... -  《-》

Constructing a Ferroptosis-related Long Non-coding RNA Signature to Predict the Prognostic of Head and Neck Squamous Cell Carcinoma Patients by Bioinformatic Analysis.

Ferroptosis is a novel discovered iron-dependent mode of regulated cell death (RCD) which characterized non-apoptosis. Researches have shown the effect of ferroptosis in the biological activities of tumors. But there is no relevant study showing the relationship between ferroptosis-related genes and head and neck squamous cell carcinoma (HNSCC). In this study, we paid attention to several ferroptosis-related lncRNAs in head and neck squamous cell carcinoma and its clinical features. HNSCC data were obtained from The Cancer Genome Atlas (TCGA) database. Ferroptosis-related lncRNAs were selected by the coexpression network. Then, we identified prognostic ferroptosis-related lncRNAs in HNSCC patients and constructed a ferroptosis-related lncRNAs signature by Lasso cox regression. Besides, GSEA analysis was performed to explore the functional enrichment of ferroptosis-related lncRNAs. Nine ferroptosis-related lncRNAs (AC004687.1, AL450992.2, AC010894.2, AL451085.2, AC104083.1, LIPE-AS1, AC108010.1, CTBP1-DT, and PTCSC2) were identified to have the independent prognostic value in HNSCC patients and the ferroptosis-related lncRNAs signature was constructed based on these nine genes. According to the risk score of the signature, the high-risk group had shorter overall survival (OS) compared with the low-risk group. Risk score showed to be an independent factor for the patients with HNSCC. Additionally, the nomogram was generated and the nine lncRNAs were mainly enriched in phagocytosis, metabolism, and chemokine signaling pathways. The ferroptosis-related lncRNA signature has effects on the prognostic prediction of patients with HNSCC which may serve as potential therapeutic targets for patients with HNSCC.

Lu R ，Li Z ，Yin S 《-》

Ferroptosis-associated DNA methylation signature predicts overall survival in patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC. Methylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients. We initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression. We established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.

Xu Y ，Hong M ，Kong D ，Deng J ，Zhong Z ，Liang J ... -  《BMC GENOMICS》

Risk model-guided identification of MTDH expression as a marker for ferroptosis induction therapy in head and neck squamous cell carcinoma.

Wang X ，Gao Y ，Miao R ，Li L ，Nanding A ，Liu Y ，Zhang X ... -  《American Journal of Cancer Research》