Prognosis Of Squamous Cell Carcinoma Research Articles

Quantified pathway mutations associate epithelial-mesenchymal transition and immune escape with poor prognosis and immunotherapy resistance of head and neck squamous cell carcinoma

BackgroundPathway mutations have been calculated to predict the poor prognosis and immunotherapy resistance in head and neck squamous cell carcinoma (HNSCC). To uncover the unique markers predicting prognosis and immune therapy response, the accurate quantification of pathway mutations are required to evaluate epithelial-mesenchymal transition (EMT) and immune escape. Yet, there is a lack of score to accurately quantify pathway mutations.Material and methodsFirstly, we proposed Individualized Weighted Hallmark Gene Set Mutation Burden (IWHMB, https://github.com/YuHongHuang-lab/IWHMB) which integrated pathway structure information and eliminated the interference of global Tumor Mutation Burden to accurately quantify pathway mutations. Subsequently, to further elucidate the association of IWHMB with EMT and immune escape, support vector machine regression model was used to identify IWHMB-related transcriptomic features (IRG), while Adversarially Regularized Graph Autoencoder (ARVGA) was used to further resolve IRG network features. Finally, Random walk with restart algorithm was used to identify biomarkers for predicting ICI response.ResultsWe quantified the HNSCC pathway mutation signatures and identified pathway mutation subtypes using IWHMB. The IWHMB-related transcriptomic features (IRG) identified by support vector machine regression were divided into 5 communities by ARVGA, among which the Community 1 enriching malignant mesenchymal components promoted EMT dynamically and regulated immune patterns associated with ICI responses. Bridge Hub Gene (BHG) identified by random walk with restart was key to IWHMB in EMT and immune escape, thus, more predictive for ICI response than other 70 public signatures.ConclusionIn summary, the novel pathway mutation scoring-IWHMB suggested that the elevated malignancy mediated by pathway mutations is a major cause of poor prognosis and immunotherapy failure in HNSCC, and is capable of identifying novel biomarkers to predict immunotherapy response.

The effect of c-Fos on the prognosis, proliferation, and invasion of oral squamous cell carcinoma.

This study aimed to determine the role of c-Fos in growth and invasion of oral squamous cell carcinoma (OSCC). Immunohistochemistry was used to assess c-Fos expression in 94 OSCC tissues and 30 adjacent normal tissues, the correlation between c-Fos expression and clinicopathological characteristics was examined, and Kaplan-Meier and Cox analysis were used to investigate the role of c-Fos in predicting the prognosis of OSCC patients. The effects of c-Fos on the growth and invasion of OSCC were disclosed by overexpression and knockdown of c-Fos. Furthermore, based on bioinformatics prediction, the effect of miR-155-5p on c-Fos expression was examined, and dual-luciferase reporter assay system was used to determine whether miR-155-5p regulated the transcriptional activity of c-Fos in OSCC. c-Fos was markedly increased in OSCC tissues and cells. c-Fos upregulation indicates a poor prognosis in OSCC patients, and c-Fos promotes cell proliferation, migration, and invasion in OSCC. miR-155-5p could regulate the expression and the transcriptional activity of c-Fos by directly targeting the c-Fos 3'-UTR. This study demonstrated that c-Fos contributed to the progression of OSCC and may act as a potential target for OSCC therapy, and a potential prognostic biomarker of OSCC.

A novel gene signature related to fatty acid metabolism predicts prognosis, immune landscape, and drug sensitivity in early-stage lung squamous cell carcinoma.

Dysregulation of fatty acid metabolism (FAM) represents a significant metabolic alteration in tumorigenesis. However, the role of FAM-related genes (FAMRGs) in early-stage lung squamous cell carcinoma (LUSC) remains incompletely understood. A series of bioinformatic analyses and machine learning strategies were performed to construct a FAMRGs-based signature to predict prognosis and guide personalized treatment for early-stage LUSC patients. FAMRGs were screened through the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the Molecular Signature Database (MSigDB). Prognosis FAMRGs were identified using univariate Cox regression, and unsupervised clustering analysis facilitated the division of the cohort into different clusters. The least absolute shrinkage and selection operator (LASSO)-Cox regression and multivariate regression analysis were employed to develop a FAMRGs-based signature for predicting overall survival (OS). A nomogram was subsequently constructed to facilitate risk assessment for individual patients. Comprehensive analyses of metabolic pathways, immune infiltration, immunomodulators, and potentially applicable drugs were conducted across different FAMRGs-related risk groups. The FAMRGs-based signature, comprising nine genes (ACOT11, APOH, BMX, CYP2R1, DPEP3, FABP6, FADS2, GLYATL2, and THRSP), demonstrated robust predictive capabilities for prognosis in The Cancer Genome Atlas (TCGA)-LUSC dataset and validated across six independent Gene Expression Omnibus (GEO)-LUSC datasets. Notably, the FAMRGs-base signature exhibited superior prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, the signature was closely associated with immune cell infiltration, human leukocyte antigen (HLA) genes, and immune checkpoint genes expression. Additionally, the signature demonstrated potential sensitivity to chemo-/target-therapy. The FAMRGs-based signature demonstrated superior sensitivity in predicting the prognosis of early-stage LUSC. Detecting FAMRGs may provide predictive targets for the development of clinical treatment strategies.

Abnormal p16 expression and prognostic significance in esophageal squamous cell carcinoma.

The purpose of this study was to analyze p16 expression status and evaluate whether abnormal p16 expression was associated with prognosis in a large-scale esophageal squamous cell carcinoma (ESCC) cohort of patients. We retrospectively evaluated p16 expression status of 525 ESCC samples using immunohistochemistry. Associations between abnormal p16 expression and survival were analyzed. P16 negative, focal expression and overexpression were found in 87.6%, 6.9% and 5.5% of ESCC patients. No significant association was observed between abnormal p16 expression and age, sex, tumor site and location, differentiation, vessel and nerve invasion, T stage and lymph node metastasis. In all patients, the survival of p16 focal expression group tended to be better compared with negative group (disease free survival/DFS P=0.040 and overall survival/OS P=0.052) and overexpression group (DFS P=0.201 and OS P=0.258), and there was no survival difference between negative group and overexpression group. The multivariate analysis for OS and DFS found that only clinical stage was a significantly independent prognostic factor (P<0.001). When patients were divided into I-II stage (n=290) and III-IVa stage (n=235), the survival of focal expression group was better compared with negative group (DFS P=0.015 and OS P=0.019), and tended to be better compared with overexpression group (DFS P=0.405 and OS P=0.432) in I-II stage ESCC, which was not found in III-IVa stage ESCC. P16 overexpression or negative expression tend to be associated with unfavorable outcomes, especially in I-II stage ESCC. Our study will help to identify a subgroup of ESCC patients with excellent prognosis after surgical therapy.

Molecular phenotypes behind patient stratification based on TP53 and HPV status and potential for treatment personalization with first single-cell RNA sequencing atlas of penile cancer.

8 Background: TP53 mutations and Human papillomavirus (HPV) have been suggested to impact penile squamous cell carcinoma (pSCC) prognosis and may predict treatment outcomes. Insights in differences in tumor micro-environment at single cell resolution may benefit personalized therapeutic development and are currently unavailable. Methods: We performed single cell RNA sequencing and targeted next generation sequencing (for TP53 loss-of-function mutations; p53LOF) on primary HPV-associated and HPV-independent (HPV+/-) pSCC lesions or healthy control samples of the coronal sulcus skin. Cell clusters were annotated based on known marker genes. Gene Set Enrichment Analysis (GSEA) and slingshot trajectory analysis was performed using R/Seurat package. Results: Twenty-two samples were analyzed: 4 tumors harbored p53LOF mutations (1 HPV+ p53LOF, 3 HPV- p53LOF), 6 HPV- p53WT, 6 HPV+ p53WT and 6 healthy controls. A total of 84.394 cells was annotated and we identified 68 distinct cell subtypes in pSCC. In epithelial cells, two distinct pseudotime trajectories stemming from the basal cells were identified characterized by either signals of partial epithelial-mesenchymal transition (pEMT; TGFB, ZEB2, SNAI2) or cornification ( ELF3, KRT19, PPL). Whilst the pEMT trajectory was enriched in p53LOF samples, cornification was enriched in HPV+ p53WT. HPV- p53WT samples displayed increase in metabolic changes and stemness hallmarks ( SOX2, HEY1, ZEB1). GSEA confirmed these findings and showed upregulation of pEMT gene sets in p53LOF; fatty acid metabolism and xenobiotic metabolism in HPV- p53WT, and cornification in HPV+ p53WT. We observed an immune suppressive environment in p53LOF patients with higher regulatory T-cell abundancy, and this correlated with abundancy in the epithelial pEMT clusters. Pseudo-bulk analysis on all T-cell subsets demonstrated a higher expression of inhibitory immune checkpoints ( PD-1, CTLA4, TIM3 and LAG3) in p53LOF and HPV- p53WT while HPV+ p53WT patients displayed higher abundancy of immunomodulatory and cytotoxic natural killer (NK) cells. Conclusions: We established the first comprehensive pSCC transcriptomic atlas at single cell resolution and illustrate differences in molecular phenotypes of pSCC according to TP53 mutation- and HPV status. p53LOF tumors are characterized by pEMT, which is a known driver of invasiveness, therapy resistance and metastasis. HPV- p53WT display hallmarks of stemness, which is related to and may explain chemotherapy-resistance often observed in these patients. p53LOF and HPV- p53WT display immune-evasion and exhaustion, while HPV+ p53WT are characterized by abundant cytotoxic innate-like lymphocytes. These observations provide deeper insights into cancer biology that will help advancing pSCC diagnosis and therapy.

A pan-cancer analysis of TTC9A expression level and its correlation with prognosis and immune microenvironment

To investigate the expression level of tetratricopeptide repeat protein 9A in tumors and its association with the patients' prognosis and immune infiltration. TTC9A expression in different tumor tissues and its association with prognosis, DNA methylation, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed based on data from TCGA and GTEx. TIMER and xCell were used to analyze the relationship between TTC9A expression and immune infiltration. Western blotting and RT-qPCR were used to detect the expression of TTC9A in 4 types of cancer cell lines. TTC9A expressions were significantly increased in many tumors and down-regulated in a few cancer types (P < 0.05). Western blotting and RT-qPCR showed that TTC9A expressions were elevated in lung, colon and liver cancer cells but decreased in bladder cancer cells. In head and neck squamous cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, low-grade glioma, malignant mesothelioma, and endometrial carcinoma tumors, a high expression of TTC9A was strongly correlated with better overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (P < 0.05), but was correlated with worse OS, DSS, and PFI in lung adenocarcinoma, pancreatic adenocarcinoma, adrenal carcinoma, and rectal adenocarcinoma (P < 0.05). TTC9A hypermethylation was associated with a more favorable prognosis of glioblastoma multiforme, low- grade glioma, uveal melanoma, and ovarian plasmacytoid cystadenocarcinoma (P < 0.05) but with poor prognosis of squamous cell carcinoma of the uterine cervix and intracervical adenocarcinoma, squamous cell carcinoma of head and neck, squamous cell carcinoma of the lungs, adrenal carcinoma, and endometrial carcinoma (P < 0.05). In most of the cancer types, TTC9A was significantly correlated with the level of immune cell infiltration (P < 0.05). TTC9A can be used as a prognostic marker for a variety of cancers and is strongly associated with TBM, MSI and immune cell infiltration.

Development and validation of glycosyltransferase related-gene for the diagnosis and prognosis of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous cancer characterized by difficulties in early diagnosis and outcome prediction. Aberrant glycosylated structures produced by the aberrant expression of glycosyltransferases are prevalent in HNSCC. In this study, we aim to construct glycosyltransferase-related gene signatures with diagnostic and prognostic value to better stratify patients with HNSCC and improve their diagnosis and prognosis. Bioinformatic tools were used to process data of patients with HNSCC from The Cancer Genome Atlas (TCGA) database. The prognostic model was formatted using univariate and multivariate Cox regression methods, while the diagnostic signature was constructed using support vector machine (SVM) and LASSO analysis. The results were verified using the Gene Expression Omnibus (GEO) cohort. The tumor microenvironment and benefits of immune checkpoint inhibitor (ICI) therapy in subgroups defined by glycosyltransferase-related genes were analyzed. Molecular biology experiments, including western blotting, cell counting kit (CCK)-8, colony formation, wound healing, and Transwell assays, were conducted to confirm the oncogenic function of beta-1,4-galactosyltransferase 3 (B4GALT3) in HNSCC. We established a five-gene prognostic signature and a 15-gene diagnostic model. Based on the median risk score, patients with low risk had longer overall survival than those in the high-risk group, which was consistent with the results of the GEO cohort. The concrete results suggested that high-risk samples were related to a high tumor protein (TP)53 mutation rate, high infiltration of resting memory cluster of differentiation (CD)4 T cells, resting natural killer (NK) cells, and M0 macrophages, and benefited from ICI therapy. In contrast, the low-risk subgroup was associated with a low TP53 mutation rate; and high infiltration of naive B cells, plasma cells, CD8 T cells, and resting mast cells; and benefited less from ICI therapy. In addition, the diagnostic model had an area under curve (AUC) value of 0.997 and 0.978 in the training dataset and validation cohort, respectively, indicating the high diagnostic potential of the model. Ultimately, the depletion of B4GALT3 significantly hindered the proliferation, migration, and invasion of HNSCC cells. We established two new biomarkers that could provide clinicians with diagnostic, prognostic, and treatment guidance for patients with HNSCC.

Analysis of the influencing factors in the long-term survival of esophageal cancer.

To analyze the prognosis and diagnostic value of relevant hematological indexes on the survival status of patients with esophageal squamous cell carcinoma after radical surgery. This study included 206 patients with esophageal cancer who underwent surgical R0 resection. The data, including the basic information, preoperative blood routine, albumin, fibrinogen, surgery-related information, postoperative pathology, and overall survival, of the patients were compared. The survival and death groups showed a significant difference in overall survival (OS), the degree of differentiation, depth of infiltration, pathological stage, vascular infiltration, nerve infiltration, fibrinogen, white blood cell, neutrophils, platelet, and platelet hematocrit (P<0.05). Tumor located in the middle thorax, larger lesion length, deeper invasion, later pathological stage, vascular infiltration, nerve infiltration, lymph node metastasis, cardiovascular disease, and higher smoking grade were risk factors for poor prognosis of esophageal squamous cell carcinoma (ESCC) (P<0.05). Cardiovascular disease, lower differentiation, tumor located in the middle thorax, and nerve infiltration were independent risk factors for the reduction of survival time of patients with ESCC (P<0.05). History of cardiovascular disease, tumor located in the middle chest, poorly differentiated esophageal squamous cell carcinoma, visible nerve cancer invasion, hematocrit (HCT), mean erythrocyte hemoglobin concentration (MCHC), and hemoglobin (HB) are independent risk factors for the long-term survival of patients with ESCC.

The analysis of multiple omics and examination of pathological images revealed the prognostic and therapeutic significances of CD93 in lung squamous cell carcinoma

As a potent pro-angiogenic factor, the role of CD93 in the prognosis and therapeutic outcomes of lung squamous cell carcinoma (LUSC) merits exploration. In this study, we systematically collected transcriptomic, genomic, and clinical data from various public databases, as well as pathological images from hospital-operated patients. Employing statistical analysis software like R (Version 4.2.2) and GraphPad (Version 8.0), we conducted comprehensive analyses of multi-omics data. The results revealed elevated CD93 expression in LUSC tissues, closely associated with various cancer-related pathways. High CD93 expression indicated advanced clinical stage and poorer prognosis. Furthermore, CD93 contributed to resistance against chemotherapy and immunotherapy by enhancing tumor cell stemness, reducing immune cell infiltration, and inducing T cell exhaustion. Patients with low CD93 expression exhibited higher response rates to both chemotherapy and immunotherapy. Immunohistochemistry validated the significance of CD93 in LUSC. CD93 emerges as a biomarker signaling unfavorable prognosis and influencing therapeutic outcomes, suggesting a potential LUSC treatment avenue.

Aberrated PSMA1 expression associated with clinicopathological features and prognosis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a globally prevalent cancer with significant mortality rates. OSCC a predominant subtype of head and neck squamous cell carcinoma (HNSCC), poses a substantial health burden. Despite advancements in diagnosis and therapy, OSCC prognosis remains poor. The 26S proteasome, a cellular protein degradation complex, is associated with cancer, including PSMA1, a proteasomal subunit, which is upregulated in various cancers. We analyzed PSMA1 expression using TCGA data, validated it in OSCC samples using real-time PCR, and explored its role through various databases. Tumor and adjacent normal tissues from OSCC patients were examined, and PSMA1 expression was analyzed. Survival analysis assessed the impact of PSMA1 on patient outcomes, while immune infiltration was examined using the TIMER database. GeneMANIA, STRING, and Metascape were utilized for gene interaction and pathway analysis. PSMA1 was significantly upregulated in OSCC and HNSCC. Its overexpression correlated with advanced clinicopathological features and poorer prognosis in HNSCC patients. PSMA1 expression is also related to immune cell infiltration. Gene interaction analysis revealed PSMA1 involvement in proteolysis regulation, suggesting its potential as a therapeutic target. PSMA1 upregulation in HNSCC association with adverse clinicopathological features and prognosis underscores its potential significance. Further research is warranted to elucidate its molecular mechanisms and therapeutic potential in OSCC management.

Value of blood oxygenation level-dependent magnetic resonance imaging in early evaluation of the response and prognosis of esophageal squamous cell carcinoma treated with definitive chemoradiotherapy: a preliminary study

BackgroundTo find a useful hypoxia non-invasive biomarker for evaluating early treatment response and prognosis to definitive chemoradiotherapy (dCRT) in patients with esophageal squamous cell carcinoma (ESCC), using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI).MethodsThe R2* values were obtained pre- and 2–3 weeks post-dCRT in 28 patients with ESCC using BOLD MRI. Independent samples t-test (normality) or Mann-Whitney U test (non-normality) was used to compare the differences of R2*-related parameters between the complete response (CR) and the non-CR groups. Diagnostic performance of parameters in predicting response was tested with receiver operating characteristic (ROC) curve analysis. The 3-year overall survival (OS) was evaluated using Kaplan Meier curve, log rank test, and Cox proportional hazards regression analysis.ResultsThe post-R2*, ∆R2*, and ∆%R2* in the CR group were significantly higher than those in the non-CR group (P = 0.002, 0.003, and 0.006, respectively). The R2*-related parameters showed good prediction of tumor response, with AUC ranging from 0.813 to 0.829. The 3-year OS rate in patients with ∆R2* >-7.54 s− 1 or CR were significantly longer than those with ∆R2* ≤ -7.54 s− 1 (72.37% vs. 0.00%; Hazard ratio, HR = 0.196; 95% confidence interval, 95% CI = 0.047–0.807; P = 0.024) or non-CR (76.47% vs. 29.27%; HR = 0.238, 95% CI = 0.059–0.963; P = 0.044).ConclusionsThe preliminary results demonstrated that the R2* value might be a useful hypoxia non-invasive biomarker for assessing response and prognosis of ESCC treated with dCRT. BOLD MRI might be used as a potential tool for evaluating tumor oxygenation metabolism, which is routinely applied in clinical practice and beneficial to clinical decision-making. A large sample size was needed for further follow-up studies to confirm the findings.

A potential new biomarker in HNSCC: metastasis suppressor protein 1 (MTSS1)

ObjectiveMetastasis suppressor protein 1 (MTSS1) is a prognostic tumour marker in different malignant epithelial tumour entities and previously mainly the MTSS1 expression was analyzed. This study evaluated the best analysis method as a prognosis and aggressiveness tumour marker in head and neck squamous cell carcinoma (HNSCC). Study DesignMTSS1 expression, MTSS1 intensity, interpretation MTSS1 score and MTSS1 edging score were analysed in formalin-fixed paraffin-embedded tissue slices of 60 patients with proven HNSCC and correlated with clinical and pathological outcome parameters. ResultsA lack of MTSS1 expression showed tumour aggressiveness, but surprisingly, mainly MTSS1 intensity was correlated with a worse patient outcome. There was a significant correlation between higher MTSS1 intensity and an increased risk for lymph node metastasis (p = 0.027) and a significant increased risk for extracapsular growth (p = 0.016). Furthermore, disease-specific survival was worse in cases with higher MTSS1 intensity (p = 0.001). ConclusionMTSS1 intensity has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision making.

Cuproptosis/OXPHOS tendency prediction of prognosis and immune microenvironment of esophageal squamous cell carcinoma: Bioinformatics analysis and experimental validation

BackgroundCuproptosis is a newly discovered cell death mechanism that relies on mitochondrial respiration, for which oxidative phosphorylation (OXPHOS) is an essential part. However, the detailed mechanisms of cuproptosis associated with OXPHOS in esophageal squamous cell carcinoma (ESCC) and how this correlation affects prognosis still remains unclear. MethodsscRNA-seq data of ESCC were downloaded from SRA (Sequence Read Archive) database. “AUCell” algorithm was used to grouping epithelial cells according to cuproptosis and OXPHOS score. Cell-cell communication, Pseudo-time Trajectory and transcription factor enrichment analysis were repectively conducted by “CellChat”, “monocle3” package and “pySCENIC” algorithm. Univariate and LASSO cox regression analysis were used to construct the prognostic cuproptosis-OXPHOS signature. Finally, CCK-8 assay and DCFH-DA staining assay were respectively validated the sensitive and ROS production of elesclomol. ResultsscRNA-seq data were analyzed to identify 10 core cell types. According to the median scores for cuproptosis and OXPHOS, malignant epithelial cells were divided into double high, double low, and mixed groups. The double high group distributed at the end of the pseudo-time trajectory and harbored HMGA1(+) as specific transcriptional regulons. Knockdown of HMGA1 partly reversed the inhibition of cell viability visualized by CCK-8 assay, while reactive oxygen species (ROS) production by elesclomol was enhanced after HMGA1 silencing. Furthermore, the immunosuppressive signal was significantly increased in the double high group detected by ‘CellChat’ in single-cell data and ‘ssGSEA’ in bulk data followed by ‘CIBERSORTx’ algorithm. Finally, a new cuproptosis-OXPHOS prognostic signature (CNN2, ATP6V0E1, PSMD6, CCDC25, IGFBP2, MT1E, and RPS4Y1) was constructed for the prediction of the prognosis, and a high-risk group corresponding to a more sensitive tendency to erlotinib, dasatinib, and bosutinib treatment was identified. ConclusionsOur study revealed the relationship between OXPHOS and tendency of cuproptosis in ESCC, and malignant cells with this characteristic exerted immunosuppressive signals and indicated poor prognosis. Furthermore, we constructed the regulatory network in high cuproptosis-OXPHOS ESCC and identified HMGA1 as a potential regulator molecule of cuproptosis mediated by elesclomol.

ALCAM is a biomarker of tumor aggressiveness and worse prognosis in glottic laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is the second most frequent head and neck tumor. Prognosis of patients with LSCC has not improved in recent decades, showing a need for the identification of prognostic biomarkers and new therapeutic targets. Recently, we showed that ALCAM overexpression was associated with glottic LSCC prognosis. Aiming to validate the prognostic value of ALCAM, we evaluate the ALCAM protein levels by immunohistochemistry in 263 glottic LSCC surgically treated with neck dissection. ALCAM was expressed in 48.7% and overexpressed in 36.5% of glottic LSCC samples. ALCAM overexpression was associated with lymph node metastasis (p = 0.030), lymphovascular involvement (p = 0.0002), high-grade tumors (p = 0.025), and tumor relapse (p = 0.043). Multivariate survival analyses showed an overfitting between ALCAM overexpression and lymph node metastasis as a prognostic variable. High ALCAM expression was associated with an aggressive glottic LSCC profile.

A novel gene signature related to focal adhesions for distinguishing and predicting the prognosis of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is a devastating and difficult-to-treat type of lung cancer, and the prognosis of LUSC is the worst. The functional roles of focal adhesion-related genes were explored in LUSC based on data from The Cancer Genome Atlas (TCGA). RNA sequencing data and clinical characteristics of LUSC patients in TCGA-LUSC were obtained from the TCGA database. Through systematic analysis, we screened the prognostic genes and determined the focal adhesion-related pathways closely associated with LUSC. We identified 444 prognostic genes and focal adhesion-related pathways intimately associated with LUSC. According to the focal adhesion-related genes, TCGA-LUSC patients were well divided into two groups: the low-risk group (G1) and the high-risk group (G2). A differential expression analysis identified 44 differentially expressed genes (DEGs) upregulated in the low-risk G1 group and 379 DEGs upregulated in the high-risk G2 group. The upregulated DEGs in the G1 group were primarily related to tyrosine metabolism, steroid hormone biosynthesis, retinol metabolism, platinum drug resistance, pentose and glucuronate interconversions, and metabolism of xenobiotics by cytochrome P450, while the downregulated DEGs in the G1 group were primarily related to ECM-receptor interaction, focal adhesion, proteoglycans in cancer, small cell lung cancer, cytokine-cytokine receptor interaction, and TGF-beta signaling pathway. The immune activity of the G1 group was lower than that of the G2 group, and the half-maximal inhibitory concentration (IC50) of five chemotherapy drugs (i.e., gemcitabine, methotrexate, vinorelbine, paclitaxel, and cisplatin) was significantly different between the G1 and G2 groups. Furthermore, a 10-gene prognostic model was constructed to predict the prognosis for LUSC patients: ITGA3, VAV2, FLNC, FLT4, HGF, MYL2, ITGB1, PDGFRA, CCND2, and PPP1CB. The status of focal adhesion-related genes has a close relationship with tumor classification and immunity in LUSC patients. A novel focal adhesion-related signature had good prognostic and predictive performance for LUSC. Our findings may provide new insight into the diagnosis and treatment of LUSC.

Development of Chromatin Regulator-related Molecular Subtypes and a Signature to Predict Prognosis and Immunotherapeutic Response in Head and Neck Squamous Cell Carcinoma.

Chromatin regulators (CRs) serve as indispensable factors in tumor biological processes by influencing tumorigenesis and the immune microenvironment and have been identified in head and neck squamous cell carcinoma (HNSCC). Hence, CR-related genes (CRRGs) are considered potential biomarkers for predicting prognosis and immune infiltration in HNSCC. In this study, we established a novel signature for predicting the prognosis and immunotherapeutic response of HSNCC. A total of 870 CRRGs were obtained according to previous studies. Subsequently, patients in the TCGA-HNSC cohort were divided into different clusters based on the expression of prognostic CRRGs. Kaplan‒Meier (K‒M) survival analysis was conducted to compare the prognosis in clusters, and the CIBERSORT and ssGSEA methods assessed the immune infiltration status. In addition, the differences in immunotherapeutic responses were determined based on the TICA database. Furthermore, the differentially expressed CRRGs between clusters were identified, and the predictive signature was established according to the results of univariate Cox, least absolute shrinkage and selection operator regression analysis, and multivariate Cox. The predictive effects of the risk model were evaluated according to the area under the receiver operating characteristic (ROC) curve (AUC) in both the training and external test cohorts. A nomogram was established, and survival comparisons, functional enrichment analyses, and immune infiltration status and clinical treatment assessments were performed. In addition, the hub gene network and related analysis were conducted with the Cytohubba application. Based on the expression of prognostic CRRGs, patients were divided into two clusters, in which Cluster 1 exhibited a better prognosis, more enriched immune infiltration, and a better immunotherapeutic response but exhibited chemotherapy sensitivity. The AUC values of the 1-, 3- and 5- year ROC curves for the risk model were 0.673, 0.732, and 0.692, respectively, as well as 0.645, 0.608, and 0.623 for the test set. In addition, patients in the low-risk group exhibited more immune cell enrichment and immune function activation, as well as a better immunotherapy response. The hub gene network indicated ACTN2 as the core gene differentially expressed between the two risk groups. We identified molecular subtypes and established a novel predictive signature based on CRRGs. This effective CRRS system can possibly provide a novel research direction for exploring the correlation between CRs and HNSCC and requires further experimental validation.

Role of E-cadherin and β-catenin in head and neck squamous cell carcinoma

Aim of the study: to present and summarize current data on the prognostic value of E-cadherin and β-catenin markers for head and neck squamous cell carcinoma, as well as to substantiate the potential benefit from implementing research results into clinical practice within the framework of a personalized approach to the treatment of head and neck squamous cell carcinoma.Material and Methods. We performed a literature search and review in Pubmed, Scopus, Google Scholar and RSCI databases regarding the association of the level of E-cadherin and β-catenin markers with disease prognosis, aggressiveness of tumor behavior and response to treatment.Results. Detailed information on the functions and mechanisms of E-cadherin and β-catenin proteins were presented and pathogenetic pathways involved in epithelial-mesenchymal transition were described. The results of studies on the association of β-catenin and E-cadherin expression levels with the prognosis of head and neck squamous cell carcinoma are collected and summarized. High expression levels of β-catenin and E-cadherin are associated with lymph node metastasis, poor prognosis and poor response to treatment.Conclusion. The expression levels of β-catenin and E-cadherin correlate with tumor invasion and lymph node metastasis, thus suggesting that β-catenin and E-cadherin can be used as potential markers of prognosis and treatment response in patients with head and neck squamous cell carcinoma. Further studies are needed to evaluate the co-expression of E-cadherin, β-catenin and other squamous cell carcinoma-associated markers, their impact on prognosis and treatment response, as well as their prognostic value.

Prediction of Prognostic Features Based on Neutrophil-Related Genes for Lung Squamous Cell Carcinoma Reveals Immune Landscape and Drug Candidates.

Background: Since to the prognosis of lung squamous cell carcinoma is generally poor, there is an urgent need to innovate new prognostic biomarkers and therapeutic targets to improve patient outcomes. Objectives: Our goal was to develop a novel multi-gene prognostic model linked to neutrophils for predicting lung squamous cell carcinoma prognosis. Methods: We utilized messenger RNA expression profiles and relevant clinical data of lung squamous cell carcinoma patients from the Cancer Genome Atlas database. Through K-means clustering, least absolute shrinkage and selection operator regression, and univariate/multivariate Cox regression analyses, we identified 12 neutrophil-related genes strongly related to patient survival and constructed a prognostic model. We verified the stability of the model in the Cancer Genome Atlas database and gene expression omnibus validation set, demonstrating the robust predictive performance of the model. Results: Immunoinfiltration analysis revealed remarkably elevated levels of infiltration for natural killer cells resting and monocytes in the high-risk group compared to the low-risk group, while macrophages had considerably lower infiltration in the high risk group. Most immune checkpoint genes, including programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4, exhibited high expression levels in the high risk group. Tumor immune dysfunction and exclusion scores and immunophenoscore results suggested a potential inclination toward immunotherapy in the "RIC" version V2 revised high risk group. Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. Conclusion: Overall, our study established a reliable prognostic risk model that possessed significant value in predicting the overall survival of lung squamous cell carcinoma patients and may guide personalized treatment strategies. (Rev Invest Clin. 2024;76(2):116-31).

Comprehensive Investigation of m6A Regulators for Prognosis in Head and Neck Squamous Cell Carcinoma.

The early detection of head and neck squamous cell carcinoma (HNSCC) has an important impact on the clinical prognosis. N6-methyladenosine (m6A) is involved in the post-transcriptional regulation of tumorigenesis and development. In this study, the prognosis and biological functions of m6A regulator targets in HNSCC were explored. RNA-Seq expression data and clinical information from TCGA-HNSCC and GSE23036 datasets were collected. The mRNA levels of IGF2BP2 and IGF2BP3 in tumor tissues were significantly up-regulated. Differential expression and functional enrichment analysis of potential targets for IGF2BP2 and IGF2BP3 obtained from the m6A2Target database showed that they were significantly enriched in cell cycle-related pathways. The Cox regression analysis was performed to establish a three-mRNA signature including PLAU, LPIN1 and AURKA. The prognostic effect was verified in the external dataset GSE41613. Further studies revealed that the three-mRNA signature was significantly associated with survival in the clinical subgroup. The ROC curve, Harrell consistency index and decision curve comparison used to compare the predictive effect of the three-mRNA signature and the other signatures in previous studies showed that the three-mRNA signature had better predictive effect on the prognosis of HNSCC patients. The three-mRNA signature expression were verified in HNSCC cell lines with qRT-PCR and Western blot. Sequence analysis showed that m6A-modification sites existed on PLAU, LPIN1 and AURKA genes. In conclusion, the three-mRNA signature has been proved to be useful on evaluating the prognosis and contributing to the personalized treatment of HNSCC, and IGB2BP2/3 were related to the cell cycle in HNSCC.

PROM2 upregulation promotes cancer cell migration and confers a poor prognosis in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) remains a difficult-to-treat disease with a poor prognosis. While prominin-1 (PROM1/CD-133) is largely investigated in a variety of malignancies, the role of prominin-2 (PROM2), the other member of the prominin family, has not been studied in LUSC. Transcriptomic data derived from matched tumor and adjacent non-tumorous lung tissues of LUSC patients were employed to conduct an in-depth analysis of the genetic and epigenetic regulation of prominin genes within LUSC, utilizing bioinformatic approaches. Furthermore, cellular behavior experiments were executed to discern the biological functions of PROM2. It was observed that PROM2, in contrast to PROM1, exhibited significant upregulation and overexpression at both the mRNA and protein levels in LUSC, and this upregulation was correlated with shortened patient survival. Transcriptomic analysis unveiled DNA methylation as an epigenetic regulatory mechanism associated with PROM2 expression. Notably, two transcription factors, CBFB and NRIP1, were identified as potential regulators of PROM2 expression. Subsequent in vitro investigations demonstrated that knocking down PROM2 led to the inhibition of cancer cell migration and the epithelial-to-mesenchymal transition (EMT). In summary, the pronounced upregulation of PROM2 in LUSC patients was linked to an unfavorable prognosis, possibly attributable to its influence on cancer cell migration and EMT. These findings suggest that PROM2 could serve as a promising diagnostic biomarker and therapeutic target in the management of LUSC. Consequently, further research into the mechanistic aspects and potential therapeutic interventions targeting PROM2 is warranted in the clinical context.