Necroptosis in Esophageal Squamous Cell Carcinoma: An Independent Prognostic Factor and Its Correlation with Tumor-Infiltrating Lymphocytes

Yamauchi, Tsuyoshi; Fujishima, Fumiyoshi; Hashimoto, Minoru; Tsunokake, Junichi; Akaishi, Ryujiro; Gokon, Yusuke; Ueki, Sadato; Ozawa, Yohei; Fukutomi, Toshiaki; Okamoto, Hiroshi; Sato, Chiaki; Taniyama, Yusuke; Nakamura, Tomohiro; Nakaya, Naoki; Kamei, Takashi; Sasano, Hironobu

doi:10.3390/cancers13174473

Cited by 11 publications

(9 citation statements)

References 44 publications

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“…Furthermore, the role of inflammation and immunity in necroptosis cannot be ignored. Biomarkers of necroptosis are significantly associated with the immunological profile in ESCA [19]. It has been reported that necroptosis induced by chemotherapy can stimulate inflammatory responses and elicit immunogenic and anticancer effects [20].…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of necroptosis-related prognostic gene signature and tumor immune microenvironment infiltration characterization in esophageal carcinoma

et al. 2022

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Background Esophageal carcinoma (ESCA) is a common malignancy with a poor prognosis. Previous research has suggested that necroptosis is involved in anti-tumor immunity and promotes oncogenesis and cancer metastasis, which in turn affects tumor prognosis. However, the role of necroptosis in ESCA is unclear. This study aimed to investigate the relationships between necroptosis-related genes (NRGs) and ESCA. Methods and results The clinical data and gene expression profiles of ESCA patients were extracted from The Cancer Genome Atlas (TCGA), and 159 NRGs were screened from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We then identified 52 differentially expressed NRGs associated with ESCA and used them for further analysis. Gene ontology (GO) and KEGG functional enrichment analyses showed that these NRGs were mostly associated with the regulation of necroptosis, Influenza A, apoptosis, NOD-like receptor, and NF-Kappa B signaling pathway. Next, univariate and multivariate Cox regression and LASSO analysis were used to identify the correlation between NRGs and the prognosis of ESCA. We constructed a prognostic model to predict the prognosis of ESCA based on SLC25A5, PPIA, and TNFRSF10B; the model classified patients into high- and low-risk subgroups based on the patient’s risk score. Furthermore, the receiver operating characteristic (ROC) curve was plotted, and the model was affirmed to perform moderately well for prognostic predictions. In addition, Gene Expression Omnibus (GEO) datasets were selected to validate the applicability and prognostic value of our predictive model. Based on different clinical variables, we compared the risk scores between the subgroups of different clinical features. We also analyzed the predictive value of this model for drug sensitivity. Moreover, Immunohistochemical (IHC) validation experiments explored that these three NRGs were expressed significantly higher in ESCA tissues than in adjacent non-tumor tissues. In addition, a significant correlation was observed between the three NRGs and immune-cell infiltration and immune checkpoints in ESCA. Conclusions In summary, we successfully constructed and validated a novel necroptosis-related signature containing three genes (SLC25A5, PPIA, and TNFRSF10B) for predicting prognosis in patients with ESCA; these three genes might also play a crucial role in the progression and immune microenvironment of ESCA.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of necroptosis-related prognostic gene signature and tumor immune microenvironment infiltration characterization in esophageal carcinoma

et al. 2022

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“…Necroptosis is a form of programmed cell death regulated by three major mediators, RIPK1, RIPK3, and MLKL ( 20 ), is a key process in cancer biology, including tumor initiation and progression, invasion and migration, and tumor immunosuppression ( 44 , 45 ). The necroptosis process is initiated by RIPK1, which then combines with RIPK3 to form an oligomeric complex called ‘necrosome’ ( 46 – 48 ).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we urgently need to analyze the clinical features, survival prognosis, tumor microenvironment, and drug sensitivity of NSCLC to further explore immune prediction efficacy and therapeutic drugs to improve the diagnosis and treatment of NSCLC (42,43). Necroptosis is a form of programmed cell death regulated by three major mediators, RIPK1, RIPK3, and MLKL (20), is a key process in cancer biology, including tumor initiation and p r o g r e s s i o n , i n v a s i on an d m i g r a t i on , a n d t u m o r immunosuppression (44,45). The necroptosis process is initiated by RIPK1, which then combines with RIPK3 to form an oligomeric complex called 'necrosome' (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Identification of molecular subtypes, risk signature, and immune landscape mediated by necroptosis-related genes in non-small cell lung cancer

Zhu

Wang

et al. 2022

Front. Oncol.

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BackgroundNon-small cell lung cancer (NSCLC) is a highly heterogeneous malignancy with an extremely high mortality rate. Necroptosis is a programmed cell death mode mediated by three major mediators, RIPK1, RIPK3, and MLKL, and has been shown to play a role in various cancers. To date, the effect of necroptosis on NSCLC remains unclear.MethodsIn The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we downloaded transcriptomes of lung adenocarcinoma (LUAD) patients and their corresponding clinicopathological parameters. We performed multi-omics analysis using consensus clustering based on the expression levels of 40 necroptosis-related genes. We constructed prognostic risk models and used the receiver operating characteristic (ROC) curves, nomograms, and survival analysis to evaluate prognostic models.ResultsWith the use of consensus clustering analysis, two distinct subtypes of necroptosis were identified based on different mRNA expression levels, and cluster B was found to have a better survival advantage. Correlation results showed that necroptosis was significantly linked with clinical features, overall survival (OS) rate, and immune infiltration. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis confirmed that these differential genes were valuable in various cellular and biological functions and were significantly enriched in various pathways such as the P53 signaling pathway and cell cycle. We further identified three genomic subtypes and found that gene cluster B patients had better prognostic value. Multivariate Cox analysis identified the 14 best prognostic genes for constructing prognostic risk models. The high-risk group was found to have a poor prognosis. The construction of nomograms and ROC curves showed stable validity in prognostic prediction. There were also significant differences in tumor immune microenvironment, tumor mutational burden (TMB), and drug sensitivity between the two risk groups. The results demonstrate that the 14 genes constructed in this prognostic risk model were used as tumor prognostic biomarkers to guide immunotherapy and chemotherapy. Finally, we used qRT-PCR to validate the genes involved in the signature.ConclusionThis study promotes our new understanding of necroptosis in the tumor microenvironment of NSCLC, mines prognostic biomarkers, and provides a potential value for guiding immunotherapy and chemotherapy.

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“…Inflammatory mediators and extracellular matrix (ECM) molecules are also a part of it, along with immune cells, endothelial cells, and mesenchymal cells [ 16 , 17 ]. In the microenvironment of tumor, immune and stromal cells are two major types of nontumor components that could be useful for the diagnosis of tumors [ 18 , 19 ]. Immune cells can help diagnose cancer, while stromal cells help predict how aggressive a tumor will become.…”

Section: Introductionmentioning

confidence: 99%

MIR548P and TRAV39 Are Potential Indicators of Tumor Microenvironment and Novel Prognostic Biomarkers of Esophageal Squamous Cell Carcinoma

Tang

Wang

et al. 2022

Journal of Oncology

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Esophageal squamous cell carcinoma (ESCC) remains a common aggressive malignancy in the world. Multiple studies have shown evidence to support the hypothesis that certain functional genes that are engaged in the microenvironment of tumors played a role in the progression of ESCC. Thus, to better analyze the prognostic values of important genes in ESCC, there is an immediate need for an in-depth research study. From the TCGA database, the RNA-seq data and clinical features of 163 ESCC patients were obtained. Using the ESTIMATE technique, we were able to calculate the ImmuneScore, the StromalScore, and the ESTIMATEScore for each ESCC sample. The samples from the ESCC were split up into high score and low score groups based on the median of the various scores. In this study, ImmuneScore, StromalScore, and ESTIMATEScore were not found to be linked with overall survival of ESCC patients, according to our findings. Higher StromalScores were linked to more advanced T stages and clinical stages. The intersection analysis that was exhibited by the use of a Venn diagram indicated that there was a total of 944 upregulated genes that shared the same high score in both the ImmuneScore and the StromalScore and that there was 0 downregulated gene that shared the same low score. Survival experiments confirmed MIR548P and TRAV39 as critical prognostic biomarkers for ESCC patients. Importantly, we found that TRAV39 expression was positively associated with T cell CD4 memory activated while negatively associated with B cell memory, dendritic cells activated, and mast cells activated. In addition, we found that MIR548P expression was negatively associated with mast cells activated while positively associated with T cell CD4 memory activated. Overall, we identified MIR548P and TRAV39 as new modulators for ESCC, affecting the immune microenvironment of ESCC patients and may be a target of immunotherapy.

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Necroptosis in Esophageal Squamous Cell Carcinoma: An Independent Prognostic Factor and Its Correlation with Tumor-Infiltrating Lymphocytes

Cited by 11 publications

References 44 publications

Identification and validation of necroptosis-related prognostic gene signature and tumor immune microenvironment infiltration characterization in esophageal carcinoma

Identification and validation of necroptosis-related prognostic gene signature and tumor immune microenvironment infiltration characterization in esophageal carcinoma

Identification of molecular subtypes, risk signature, and immune landscape mediated by necroptosis-related genes in non-small cell lung cancer

MIR548P and TRAV39 Are Potential Indicators of Tumor Microenvironment and Novel Prognostic Biomarkers of Esophageal Squamous Cell Carcinoma

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