Bioinformatics analysis of necroptosis‑related lncRNAs and immune infiltration, and prediction of the prognosis of patients with esophageal carcinoma

Esophageal carcinoma (ESCA) is one of the most common malignancies in the world, and has high morbidity and mortality rates. Necrosis and long noncoding RNAs (lncRNAs) are involved in the progression of ESCA; however, the specific mechanism has not been clarified. The aim of the present study was to investigate the role of necrosis-related lncRNAs (nrlncRNAs) in patients with ESCA by bioinformatics analysis, and to establish a nrlncRNA model to predict ESCA immune infiltration and prognosis. To form synthetic matrices, ESCA transcriptome data and related information were obtained from The Cancer Genome Atlas. A nrlncRNA model was established by coexpression, univariate Cox (Uni-Cox), and least absolute shrinkage and selection operator analyses. The predictive ability of this model was evaluated by Kaplan-Meier, receiver operating characteristic (ROC) curve, Uni-Cox, multivariate Cox regression, nomogram and calibration curve analyses. A model containing eight nrlncRNAs was generated. The areas under the ROC curves for 1-, 3- and 5-year overall survival were 0.746, 0.671 and 0.812, respectively. A high-risk score according to this model could be used as an indicator for systemic therapy use, since the half-maximum inhibitory concentration values varied significantly between the high-risk and low-risk groups. Based on the expression of eight prognosis-related nrlncRNAs, the patients with ESCA were regrouped using the ‘ConsensusClusterPlus’ package to explore potential molecular subgroups responding to immunotherapy. The patients with ESCA were divided into three clusters based on the eight nrlncRNAs that constituted the risk model: The most low-risk group patients were classified into cluster 1, and the high-risk group patients were mainly concentrated in clusters 2 and 3. Survival analysis showed that Cluster 1 had a better survival than the other groups (P=0.016). This classification system could contribute to precision treatment. Furthermore, two nrlncRNAs (LINC02811 and LINC00299) were assessed in the esophageal epithelial cell line HET-1A, and in the human esophageal cancer cell lines KYSE150 and TE1. There were significant differences in the expression levels of these lncRNAs between tumor and normal cells. In conclusion, the present study suggested that nrlncRNA models may predict the prognosis of patients with ESCA, and provide guidance for immunotherapy and chemotherapy decision making. Furthermore, the present study provided strategies to promote the development of individualized and precise treatment for patients with ESCA.

[1]  Yi Shen,et al.  Construction of a necroptosis‐related lncRNA signature to predict the prognosis and immune microenvironment of head and neck squamous cell carcinoma , 2022, Journal of clinical laboratory analysis.

[2]  Zhengrong Li,et al.  A Necroptosis-Related lncRNA-Based Signature to Predict Prognosis and Probe Molecular Characteristics of Stomach Adenocarcinoma , 2022, Frontiers in Genetics.

[3]  Shirong Cao,et al.  Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis , 2022, Molecular cancer.

[4]  Y. Sheng,et al.  Necroptosis‐related lncRNA to establish novel prognostic signature and predict the immunotherapy response in breast cancer , 2022, Journal of clinical laboratory analysis.

[5]  Chenbo Yang,et al.  Long Non-Coding RNA in Esophageal Cancer: A Review of Research Progress , 2022, Pathology & Oncology Research.

[6]  Z. Jie,et al.  Comprehensive Analysis of Necroptosis-Related Long Noncoding RNA Immune Infiltration and Prediction of Prognosis in Patients With Colon Cancer , 2022, Frontiers in Molecular Biosciences.

[7]  Xingyu Zhou,et al.  Necroptosis-Related lncRNAs: Predicting Prognosis and the Distinction between the Cold and Hot Tumors in Gastric Cancer , 2021, Journal of oncology.

[8]  S. Koyama,et al.  Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies , 2021, Journal for ImmunoTherapy of Cancer.

[9]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[10]  Jingdun Xie,et al.  Immune-Related lncRNA to Construct Novel Signature and Predict the Immune Landscape of Human Hepatocellular Carcinoma , 2020, Molecular therapy. Nucleic acids.

[11]  Y. Kakeji,et al.  Multimodality approaches to control esophageal cancer: development of chemoradiotherapy, chemotherapy, and immunotherapy , 2020, Esophagus.

[12]  M. Gazouli,et al.  MALAT1 as a Versatile Regulator of Cancer: Overview of the updates from Predatory role as Competitive Endogenous RNA to Mechanistic In-sights. , 2020, Current Cancer Drug Targets.

[13]  O. Fletcher,et al.  DNA methylation of the long intergenic noncoding RNA 299 gene in triple-negative breast cancer: results from a prospective study , 2020, Scientific Reports.

[14]  L. Guiqing,et al.  Long non-coding RNA LINC00299 knockdown inhibits ox-LDL-induced T/G HAVSMC injury by regulating miR-135a-5p/XBP1 axis in atherosclerosis. , 2020, Panminerva medica.

[15]  Lydia Y. Liu,et al.  LncRNA ZEB2-AS1 promotes the proliferation, migration and invasion of esophageal squamous cell carcinoma cell through miR-574-3p/HMGA2 axis. , 2020, European review for medical and pharmacological sciences.

[16]  Yi Zeng,et al.  A transcriptomic analysis of malignant transformation of human embryonic esophageal epithelial cells by HPV18 E6E7 , 2020, Translational cancer research.

[17]  J. Ajani,et al.  Non-coding RNAs in GI cancers: from cancer hallmarks to clinical utility , 2020, Gut.

[18]  J. Ajani,et al.  LncRNA PVT1 up-regulation is a poor prognosticator and serves as a therapeutic target in esophageal adenocarcinoma , 2019, Molecular Cancer.

[19]  D. Baker,et al.  Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity , 2019, Science Immunology.

[20]  Chao Yang,et al.  The role of necroptosis in cancer biology and therapy , 2019, Molecular Cancer.

[21]  Yong Liu,et al.  Linc00299/miR-490-3p/AURKA axis regulates cell growth and migration in atherosclerosis , 2019, Heart and Vessels.

[22]  D. Liu,et al.  High-throughput sequencing reveals differentially expressed lncRNAs and circRNAs, and their associated functional network, in human hypertrophic scars , 2018, Molecular medicine reports.

[23]  Chengyu Liu,et al.  Necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis , 2018, Cell Research.

[24]  Anhui Wang Epidemiology of Esophageal Squamous Cell Carcinoma , 2018 .

[25]  Eva Seligman On death and survival , 2018 .

[26]  P. Vandenabeele,et al.  Necroptotic cell death in anti‐cancer therapy , 2017, Immunological reviews.

[27]  Zhijun Li,et al.  Long noncoding RNA MALAT1 affects the efficacy of radiotherapy for esophageal squamous cell carcinoma by regulating Cks1 expression , 2017, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[28]  Jiahuai Han,et al.  2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter. , 2017, Cell reports.

[29]  M. Pasparakis,et al.  Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis , 2016, Nature.

[30]  W. Weichert,et al.  RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells. , 2016, Cancer cell.

[31]  A. Iuga,et al.  Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis , 2016, Oncotarget.

[32]  L. Zitvogel,et al.  Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  Chuan-Yuan Li,et al.  Key roles of necroptotic factors in promoting tumor growth , 2016, Oncotarget.

[34]  R. Lerner,et al.  Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling , 2015, Nature Communications.

[35]  A. Thorburn,et al.  Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics , 2015, Cell Research.

[36]  S. Okada,et al.  PolyI:C–Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector–Mediated Tumor Elimination In Vivo , 2015, Cancer Immunology Research.

[37]  R. Bohle,et al.  RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation , 2015, Oncotarget.

[38]  C. Baines,et al.  Necroptosis: is there a role for mitochondria? , 2014, Front. Physiol..

[39]  B. Quesnel,et al.  RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage , 2014, Cell Death and Disease.

[40]  S. Misra,et al.  Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. , 2014, World journal of gastrointestinal oncology.

[41]  N. Cox,et al.  Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines , 2014, Genome Biology.

[42]  Yiping Shen,et al.  Disruption of a large intergenic noncoding RNA in subjects with neurodevelopmental disabilities. , 2012, American journal of human genetics.

[43]  R. Korneluk,et al.  cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation , 2012, Cell Death and Differentiation.

[44]  P. Vandenabeele,et al.  RIP Kinases at the Crossroads of Cell Death and Survival , 2009, Cell.

[45]  Alexei Degterev,et al.  Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury , 2005, Nature chemical biology.

[46]  W. Kolch,et al.  The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting miR-873 , 2016, Cell Death and Differentiation.

[47]  Peter D Siersema,et al.  Esophageal cancer. , 2008, Gastroenterology clinics of North America.