文献检索，用中文搜 PubMed

INTRODUCTION

Cancer's inherent heterogeneity, marked by diverse genetic and molecular alterations, presents significant challenges for developing effective treatments. One such alteration is the regulation of disulfidoptosis, a recently discovered programmed cell death pathway. RPN1, a key regulator associated with disulfidoptosis, may influence various aspects of tumor biology, including immune evasion and cellular senescence. This study aims to dissect the role of RPN1 in pan-cancer and its potential as a therapeutic target.

METHODS

We employed a pan-cancer analysis to explore RPN1 expression and its association with clinical outcomes across multiple tumor types. Immune cell infiltration and expression of immune checkpoint genes were analyzed in relation to RPN1. Additionally, cellular senescence markers were assessed in RPN1 knockdown tumor cells. Gene regulatory mechanisms were studied through gene copy number variations, DNA methylation analysis, and transcriptional regulation by SP1.

RESULTS

RPN1 is overexpressed in a wide range of tumor types and correlates with poor clinical outcomes, including overall survival, disease-specific survival, and progression-free intervals. Our analysis shows that RPN1 is involved in immune evasion, correlating with the presence of myeloid dendritic cells, macrophages, and tumor-associated fibroblasts, and influencing T-cell activity. RPN1 knockdown led to reduced tumor cell proliferation and induced cellular senescence, marked by increased senescence-associated biomarkers and β-galactosidase activity. RPN1 expression was found to be regulated by gene copy number variations, reduced DNA methylation, and transcriptional control via SP1.

DISCUSSION

These findings highlight RPN1 as a key pan-cancer regulator, influencing immune microenvironment interactions and cellular senescence. The regulation of disulfidoptosis by RPN1 presents a promising avenue for therapeutic intervention. Targeting RPN1 could enhance immunotherapy efficacy and help mitigate tumor progression, offering a potential strategy for cancer treatment.

INTRODUCTION

METHODS

RESULTS

DISCUSSION

引言

癌症固有的异质性以多样的基因和分子改变为特征，这给开发有效的治疗方法带来了重大挑战。其中一种改变是二硫键介导的细胞凋亡的调控，这是一种最近发现的程序性细胞死亡途径。RPN1是与二硫键介导的细胞凋亡相关的关键调节因子，可能影响肿瘤生物学的各个方面，包括免疫逃逸和细胞衰老。本研究旨在剖析RPN1在泛癌中的作用及其作为治疗靶点的潜力。

方法

我们采用泛癌分析来探究RPN1在多种肿瘤类型中的表达及其与临床结局的关联。分析了与RPN1相关的免疫细胞浸润和免疫检查点基因的表达。此外，还评估了RPN1敲低的肿瘤细胞中的细胞衰老标志物。通过基因拷贝数变异、DNA甲基化分析以及SP1的转录调控来研究基因调控机制。

结果

RPN1在多种肿瘤类型中均有过表达，且与不良临床结局相关，包括总生存期、疾病特异性生存期和无进展生存期。我们的分析表明，RPN1参与免疫逃逸，与髓样树突状细胞、巨噬细胞和肿瘤相关成纤维细胞的存在相关，并影响T细胞活性。RPN1敲低导致肿瘤细胞增殖减少并诱导细胞衰老，表现为衰老相关生物标志物和β-半乳糖苷酶活性增加。发现RPN1的表达受基因拷贝数变异、DNA甲基化减少以及通过SP1的转录控制所调节。