Comprehensive analysis of necroptosis-related lncRNA signature with potential implications in tumor heterogeneity and prediction of prognosis in clear cell renal cell carcinoma.

Necroptosis has been reported to play a critical role in occurrence and progression of cancer. The dysregulation of long non-coding RNAs (lncRNAs) is associated with the progression and metastasis of clear cell renal cell carcinoma (CCRCC). However, research on necroptosis-related lncRNAs in the tumor heterogeneity and prognosis of CCRCC is not completely unclear. This study aimed to analysis the tumor heterogeneity among CCRCC subgroups and construct a CCRCC prognostic signature based on necroptosis-related lncRNAs. Weighted gene co-expression network analysis (WGCNA) was performed to identify necroptosis-related lncRNAs. A preliminary classification of molecular subgroups was performed by non-negative matrix factorization (NMF) consensus clustering analysis. Comprehensive analyses, including fraction genome altered (FGA), tumor mutational burden (TMB), DNA methylation alterations, copy number variations (CNVs), and single nucleotide polymorphisms (SNPs), were performed to explore the potential factors for tumor heterogeneity among the three subgroups. Subsequently, we constructed a predictive signature by multivariate Cox regression. Nomogram, calibration curves, decision curve analysis (DCA), and time-dependent receiver-operating characteristics (ROC) were used to validate and evaluate the signature. Finally, immune correlation analyses, including immune-related signaling pathways, immune cell infiltration status and immune checkpoint gene expression level, were also performed. Seven necroptosis-related lncRNAs were screened out by WGCNA, and three subgroups were classified by NMF consensus clustering analysis. There were significant differences in survival prognosis, clinicopathological characteristics, enrichments of immune-related signaling pathway, degree of immune cell infiltration, and expression of immune checkpoint genes in the various subgroups. Most importantly, we found that 26 differentially expressed genes (DEGs) among the 3 subgroups were not affected by DNA methylation alterations, CNVs and SNPs. On the contrary, these DEGs were associated with the seven necroptosis-related lncRNAs. Subsequently, the identified RP11-133F8.2 and RP11-283G6.4 by multivariate Cox regression analysis were involved in the risk model, which could serve as an independent prognostic factor for CCRCC. Finally, qRT-PCR confirmed the differential expression of the two lncRNAs. These findings contributed to understanding the function of necroptosis-related lncRNAs in CCRCC and provided new insights of prognostic evaluation and optimal therapeutic strategy for CCRCC.

Lin H ，Qu L ，Chen G ，Zhang C ，Lu L ，Chen Y ... -  《-》

A novel necroptosis-related long noncoding RNA model for predicting clinical features, immune characteristics, and therapeutic response in clear cell renal cell carcinoma.

Necroptosis is an immune-related cell death pathway involved in the regulation of the tumor microenvironment (TME). Here, we aimed to explore the role of necroptosis in clear cell renal cell carcinoma (ccRCC) and construct a necroptosis-related lncRNA (NRL) model to assess its potential association with clinical characteristics and immune status. Gene expression profiles and clinical data for ccRCC patients were obtained from the Cancer Genome Atlas (TCGA). Pearson's correlation, univariate Cox, and least absolute shrinkage and selection operator analyses were used to develop an NRL model. Kaplan-Meier (K-M) and receiver operating characteristic (ROC) curve analyses were used to determine the prognostic value of the NRL model. The clinical information was used to assess the diagnostic value of the NRL model. The TME, immune function, immune cell infiltration, and immune checkpoints associated with the NRL model risk score were studied using the ESTIMATE, GSEA, ssGSEA, and CIBERSORT algorithms. The immunophenoscore (IPS) and half-maximal inhibitory concentration (IC50) were used to compare the efficacies of immunotherapy and chemotherapy based on the NRL model. Finally, in vitro assays were performed to confirm the biological roles of NRLs. A total of 18 necroptosis-related genes and 285 NRLs in ccRCC were identified. A four-NRL model was constructed and showed good performance in the diagnosis and prognosis of ccRCC patients. The ESTIMATE scores, tumor mutation burden, and tumor stemness indices were significantly correlated with NRL model risk score. Immune functions such as chemokine receptors and immune receptor activity showed differences between different risk groups. The infiltration of immunosuppressive cells such as Tregs was higher in high-risk patients than in low-risk patients. High-risk patients were more sensitive to immunotherapy and some chemotherapy drugs, such as sunitinib and temsirolimus. Finally, the expression of NRLs included in the model was verified, and knocking down these NRLs in tumor cells affected cell proliferation, migration, and invasion. Necroptosis plays an important role in the progression of ccRCC. The NRL model we constructed can be used to predict the clinical characteristics and immune features of ccRCC patients.

Zhang L ，Chen Y ，Hu W ，Wu B ，Ye L ，Wang D ，Bai T ... -  《Frontiers in Immunology》

A novel necroptosis-related lncRNAs signature for survival prediction in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common kind of kidney cancer with poor prognosis. Necroptosis is a newly observed type of programmed cell death in recent years. However, the effects of necroptosis-related lncRNAs (NRlncRNAs) on ccRCC have not been widely explored. The transcription profile and clinical information were obtained from The Cancer Genome Atlas. Necroptosis-related lncRNAs were identified by utilizing a co-expression network of necroptosis-related genes and lncRNAs. Univariate Cox regression, least absolute shrinkage, and selection operator regression and multivariate Cox regression were performed to screen out ideal prognostic necroptosis-related lncRNAss and develop a multi-lncRNA signature. Finally, 6 necroptosis-related lncRNA markers were established. Patients were separated into high- and low-risk groups based on the performance value of the median risk score. Kaplan-Meier analysis identified that high-risk patients had poorer prognosis than low-risk patients. Furthermore, the area under time-dependent receiver operating characteristic curve reached 0.743 at 1 year, 0.719 at 3 years, and 0.742 at 5 years, which indicating that they can be used to predict ccRCC prognosis. In addition, the proposed signature was related to immunocyte infiltration. A nomogram model was also established to provide a more beneficial prognostic indicator for the clinic. Altogether, in the present study, the 6-lncRNA prognostic risk signature are trustworthy and effective indicators for predicting the prognosis of ccRCC.

Zhao L ，Luo H ，Dong X ，Zeng Z ，Zhang J ，Yi Y ，Lin C ... -  《-》

Clinicopathological and Prognostic Value of Necroptosis-Associated lncRNA Model in Patients with Kidney Renal Clear Cell Carcinoma.

Necroptosis, a recently identified type of programmed necrotic cell death, is closely related to the tumorigenesis and development of cancer. However, it remains unclear whether necroptosis-associated long noncoding RNAs (lncRNAs) can be used to predict the prognosis of kidney renal clear cell carcinoma (KIRC). This work was designed to probe the possible prognostic worth of necroptosis-associated lncRNAs along with their impact on the tumor microenvironment (TME) in KIRC. The Cancer Genome Atlas (TCGA) database was used to extract KIRC gene expression and clinicopathological data. Pearson correlation analysis was used to evaluate necroptosis-associated lncRNAs against 159 known necroptosis-associated genes. To define molecular subtypes, researchers used univariate Cox regression analysis and consensus clustering, as well as clinical significance, TME, and tumor immune cells in each molecular subtype. We develop the necroptosis-associated lncRNA prognostic model using univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) regression analysis. Patients were divided into high- and low-risk groups according to prognostic model. Moreover, comprehensive analyses, including prognostic value, gene set enrichment analysis (GSEA), immune infiltration, and immune checkpoint gene expression, were performed between the two risk groups. Finally, anticancer drug sensitivity analyses were employed for assessing associations for necroptosis-associated lncRNA expression profile and anticancer drug chemosensitivity. Through univariate analysis, sixty-nine necroptosis-associated lncRNAs were found to have a significant relationship with KIRC prognosis. Two molecular clusters were identified, and significant differences were found with respect to clinicopathological features and prognosis. The segregation of patients into two risk groups was done by the constructed necroptosis-associated lncRNA model. The survival prognosis, clinical features, degree of immune cell infiltration, and expression of immune checkpoint genes of high-risk and low-risk groups were all shown to vary. Our study identified a model of necroptosis-associated lncRNA signature and revealed its prognostic role in KIRC. It is expected to provide a reference for the screening of KIRC prognostic markers and the evaluation of immune response.

Gu J ，He Z ，Huang Y ，Luan T ，Chen Z ，Wang J ，Ding M ... -  《-》

Development of a novel disulfidptosis-related lncRNA signature for prognostic and immune response prediction in clear cell renal cell carcinoma.

Wang N ，Hu Y ，Wang S ，Xu Q ，Jiao X ，Wang Y ，Yan L ，Cao H ，Shao F ... -  《Scientific Reports》