Identification of cuproptosis -related subtypes, the development of a prognosis model, and characterization of tumor microenvironment infiltration in prostate cancer

Abstract

Cuproptosis, Copper Induced Cell Death, is a newly defined type of programmed cell death, involving in the regulation of tricarboxylic acid (TCA) cycle. Dysfunction of cuproptosis induces cytotoxicity and influences the proliferation of multiple tumors. However, the direct prognostic effect of cuproptosis related genes and corresponding regulating mechanisms amid prostate cancer remains unknown. A multi-omics analysis strategy was adopted to explore the role of ten cuproptosis related genes in The Cancer Genome Atlas- Prostate Adenocarcinoma (TCGA-PRAD). Firstly, mRNA expression, Copy Number Variance (CNV), mutation, DNA methylation and prognostic power of the ten genes were illustrated. Based on transcriptomic data, we developed a novel prognostic model named the Cuproptosis-related gene score (CRGScore), Their biological functions were then detected by enrichment analysis and unsupervised cluster analysis. Following that, their correlation with Tumor Immune Microenvironment (TIME), immunotherapy, Biochemical Recurrence (BCR) and chemotherapeutic resistance were elaborated by relevant bioinformatics algorithms. Ten cuproptosis related genes exhibited extensive alteration of CNV and DNA methylation and showed significant influence on the prognosis of prostate cancer patients. These genes mainly enriched in E2F and G2M targets and mitosis pathways, Samples with high CRGScore showed enhancement resulting in the increased infiltration of T cell, B cell, NK cells. They also demonstrated close correlations with the BCR status, expression of eight immune checkpoints and chemotherapeutic resistances in prostate cancer. Our comprehensive analysis of CRGScore revealed an extensive regulatory mechanism by which they affect the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. We also determined the therapeutic liability of CRGScore in targeted therapy and immunotherapy. These findings highlight the crucial clinical implications of CRGScore and provide new ideas for guiding personalized immunotherapy strategies for patients with Pca.

Identification and validation of a novel cuproptosis-related lncRNA gene signature to predict prognosis and immune response in bladder cancer

“…According to the current study, a novel signature based on the cuproptosis gene may be able to predict a patient's prognosis, biological makeup, and the best course of therapy for them if they have glioma or triple negative breast cancer [43,44]. The immune microenvironment and tumor immunotherapy may both be affected by cuproptosis-related lncRNAs at the same time [45][46][47].…”

Cuproptosis-related lncRNA signature for prognostic prediction in patients with acute myeloid leukemia

“…The functional role of cuproptosis in cancer development has been previously reported. For example, cuproptosis was used to predict clinical outcomes and immune response in bladder cancer [9], breast cancer [10], colorectal cancer [11], and prostate cancer [12]. A more recent study suggested that cuproptosis-related genes might be critically involved in the 2-year AML prognosis and the immune response to treatment [13].…”

Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT/mTOR pathway in prostate cancer

“…12 Numerous cuproptosis-related genes, such as DLAT, showed considerable changes in DNA methylation and CNV, which had a significant impact on the prognosis of patients with PCa. 13 However, the role of cuproptosis in regulating Doce resistance remains unclear.…”

“…Furthermore, copper(II) bis (diethyldithiocarbamate)‐based nanoparticles demonstrated anti‐GSH cytotoxicity with an efficient reversal of the resistance to cisplatin, whereas GSH detoxified the lethal impact of cisplatin in A549 cells 12 . Numerous cuproptosis‐related genes, such as DLAT, showed considerable changes in DNA methylation and CNV, which had a significant impact on the prognosis of patients with PCa 13 . However, the role of cuproptosis in regulating Doce resistance remains unclear.…”