Deciphering a Novel Necroptosis-Related miRNA Signature for Predicting the Prognosis of Clear Cell Renal Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common histological and devastating subtype of renal cell carcinoma. Necroptosis is a form of programmed cell death that causes prominent inflammatory responses. miRNAs play a significant role in cancer progression through necroptosis. However, the prognostic value of necroptosis-related miRNAs remains ambiguous. In this study, 39 necroptosis-related miRNAs (NRMs) were extracted and 17 differentially expressed NRMs between normal and tumor samples were identified using data form The Cancer Genome Atlas (TCGA). After applying univariate Cox proportional hazard regression analysis and LASSO Cox regression model, six necroptosis-related miRNA signatures were identified in the training cohort and their expression levels were verified by qRT-PCR. Using the expression levels of these miRNAs, all patients were divided into the high- and low-risk groups. Patients in the high-risk group showed poor overall survival ( P < 0.0001 ). Time-dependent ROC curves confirmed the good performance of our signature. The results were verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression models demonstrated that the risk score was an independent prognostic factor. Additionally, a predictive nomogram with good performance was constructed to enhance the implementation of the constructed signature in a clinical setting. We then employed miRBD, miRTarBase, and TargetScan to predict the target genes of six necroptosis-related miRNAs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that 392 potential target genes were enriched in cell proliferation-related biological processes. Six miRNAs and 59 differentially expressed target genes were used to construct an miRNA–mRNA interaction network, and 11 hub genes were selected for survival and tumor infiltration analysis. Drug sensitivity analysis revealed potential drugs that may contribute to cancer management. Hence, necroptosis-related genes play an important role in cancer biology. We developed, for the first time, a necroptosis-related miRNA signature to predict ccRCC prognosis.

Establishment of a Novel Prognostic Prediction Model for Gastric Cancer Based on Necroptosis-Related Genes

“…On the other hand, necroptosis provides a favorable environment for tumor proliferation and metastasis [ 6 ]. Nowadays, necroptosis-related signatures have been built in several types of cancer [ 8 , 19 , 20 ]. Our study mainly investigated whether NAGs are correlated with the prognosis of GC and whether they could predict patient responses to immunotherapy.…”

“…Hence, necroptosis is expected to become a new target for cancer therapy. In recent years, gene expression signatures based on necroptosis-associated genes (NAGs) have been reported to predict the prognosis of several types of cancer, including colon cancer, clear cell renal carcinoma, breast cancer, and lung cancer [8][9][10][11]. However, a necroptosis-associated model in GC is lacking.…”

Role of microRNAs in programmed cell death in renal diseases: A review

“…[ 75 ] Recently, a novel miRNA signature of the necroptosis phase for predicting the prognosis of clear cell renal cancer was reported, and after a series of assays and analyses, 6 necroptosis-related miRNAs in the risk profile were finally explored (has-miR-101-3p, has-miR-193a-3p, has-miR-200a-5p, has-miR-214-3p, has-miR-221-3p, has-miR-223-3p). [ 76 ] (Table 3 )…”

Modulation of AKT Pathway-Targeting miRNAs for Cancer Cell Treatment with Natural Products

“…miRNAs are responsible for post-transcriptional gene regulation and are classified according to their oncogenic and tumor suppression functions in the regulation of diverse cell functions [ 1 ]. miRNAs are known to have several functions in the regulation of proliferation, apoptosis [ 2 ], autophagy [ 3 , 4 , 5 ], endoplasmic reticulum (ER) stress [ 1 , 6 ], ferroptosis [ 7 , 8 , 9 , 10 ], necroptosis [ 11 , 12 , 13 , 14 ], DNA damage response (DDR) [ 15 , 16 , 17 ], senescence [ 18 , 19 ], and migration [ 20 , 21 , 22 , 23 ] relating to cancer cells [ 23 , 24 , 25 ]. In the following, we briefly introduce the background for these cell functions and their relationships to miRNA.…”

“…Necroptosis refers to the nonapoptosis-programmed, necrosis-based cell death involving receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) protein. Some miRNAs upregulate and downregulate necroptosis in the liver [ 11 ], kidneys [ 12 ], and lungs [ 13 ], as well as in colon cancer [ 14 ].…”