Li Na, Zhan Xianquan
Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong 250117 People's Republic of China.
Medical Science and Technology Innovation Center, Shandong First Medical University, 6699 Qingdao Road, Jinan, Shandong 250117 People's Republic of China.
EPMA J. 2021 Sep 30;12(4):605-627. doi: 10.1007/s13167-021-00256-z. eCollection 2021 Dec.
Proteasome, a cylindrical complex containing 19S regulatory particle lid, 19S regulatory particle base, and 20S core particle, acted as a major mechanism to regulate the levels of intracellular proteins and degrade misfolded proteins, which involved in many cellular processes, and played important roles in cancer biological processes. Elucidation of proteasome alterations across multiple cancer types will directly contribute to cancer medical services in the context of predictive, preventive, and personalized medicine (PPPM / 3P medicine).
This study aimed to investigate proteasome gene alterations across 33 cancer types for discovery of effective biomarkers and therapeutic targets in the framework of PPPM practice in cancers.
Proteasome gene data, including gene expression RNAseq, somatic mutation, tumor mutation burden (TMB), copy number variant (CNV), microsatellite instability (MSI) score, clinical characteristics, immune phenotype, 22 immune cells, cancer stemness index, drug sensitivity, and related pathways, were systematically analyzed with publically available database and bioinformatics across 11,057 patients with 33 cancer types.
Differentially expressed proteasome genes were extensively found between tumor and control tissues. PSMB4 occurred the top mutation event among proteasome genes, and those proteasome genes were significantly associated with TMB and MSI score. Most of proteasome genes were positively related to CNV among single deletion, control copy number, and single gain. Kaplan-Meier curves and COX regression survival analysis showed proteasome genes were significantly associated with patient survival rate across 33 cancer types. Furthermore, the expressions of proteasome genes were significantly different among different clinical stages and immune subtypes. The expressions of proteasome genes were correlated with immune-related scores (ImmuneScore, StromalScore, and ESTIMATEScore), 22 immune cells, and cancer stemness. The sensitivities of multiple drugs were closely related to proteasome gene expressions. The identified proteasome and proteasome-interacted proteins were significantly enriched in various cancer-related pathways.
This study provided the first landscape of proteasome alterations across 11,057 patients with 33 cancer types and revealed that proteasome played a significant and wide functional role in cancer biological processes. These findings are the precious scientific data to reveal the common and specific alterations of proteasome genes among 33 cancer types, which benefits the research and practice of PPPM in cancers.
The online version contains supplementary material available at 10.1007/s13167-021-00256-z.
蛋白酶体是一种包含19S调节颗粒盖子、19S调节颗粒底座和20S核心颗粒的圆柱形复合物，是调节细胞内蛋白质水平和降解错误折叠蛋白质的主要机制，参与许多细胞过程，并在癌症生物学过程中发挥重要作用。阐明多种癌症类型中蛋白酶体的改变将直接有助于在预测、预防和个性化医学（PPPM/3P医学）背景下的癌症医疗服务。
本研究旨在调查33种癌症类型中的蛋白酶体基因改变，以在癌症的PPPM实践框架内发现有效的生物标志物和治疗靶点。
利用公开可用的数据库和生物信息学方法，对11057例患有33种癌症类型的患者的蛋白酶体基因数据进行系统分析，这些数据包括基因表达RNAseq、体细胞突变、肿瘤突变负荷（TMB）、拷贝数变异（CNV）、微卫星不稳定性（MSI）评分、临床特征、免疫表型、22种免疫细胞、癌症干性指数、药物敏感性及相关通路。
在肿瘤组织和对照组织之间广泛发现了差异表达的蛋白酶体基因。PSMB4在蛋白酶体基因中发生的突变事件最多，且这些蛋白酶体基因与TMB和MSI评分显著相关。在单倍体缺失、对照拷贝数和单倍体增加中，大多数蛋白酶体基因与CNV呈正相关。Kaplan-Meier曲线和COX回归生存分析表明，蛋白酶体基因与33种癌症类型患者的生存率显著相关。此外，蛋白酶体基因的表达在不同临床阶段和免疫亚型之间存在显著差异。蛋白酶体基因的表达与免疫相关评分（免疫评分、基质评分和ESTIMATE评分）、22种免疫细胞和癌症干性相关。多种药物的敏感性与蛋白酶体基因表达密切相关。鉴定出的蛋白酶体和与蛋白酶体相互作用的蛋白质在各种癌症相关通路中显著富集。
本研究提供了11057例患有33种癌症类型患者的蛋白酶体改变的首张全景图，并揭示了蛋白酶体在癌症生物学过程中发挥着重要且广泛的功能作用。这些发现是揭示33种癌症类型中蛋白酶体基因常见和特异性改变的宝贵科学数据，有利于癌症PPPM的研究和实践。
在线版本包含可在10.1007/s13167-021-00256-z获取的补充材料。
