Cellular senescence and metabolic reprogramming model based on bulk/single-cell RNA sequencing reveals PTGER4 as a therapeutic target for ccRCC

Author:

Zhou Lijie,Zeng Youmiao,Liu Yuanhao,Du Kaixuan,Luo Yongbo,Dai Yiheng,Pan Wenbang,Zhang Lailai,Zhang Lei,Tian Fengyan,Gu Chaohui

Abstract

AbstractClear cell renal cell carcinoma (ccRCC) is the prevailing histological subtype of renal cell carcinoma and has unique metabolic reprogramming during its occurrence and development. Cell senescence is one of the newly identified tumor characteristics. However, there is a dearth of methodical and all-encompassing investigations regarding the correlation between the broad-ranging alterations in metabolic processes associated with aging and ccRCC. We utilized a range of analytical methodologies, such as protein‒protein interaction network analysis and least absolute shrinkage and selection operator (LASSO) regression analysis, to form and validate a risk score model known as the senescence-metabolism-related risk model (SeMRM). Our study demonstrated that SeMRM could more precisely predict the OS of ccRCC patients than the clinical prognostic markers in use. By utilizing two distinct datasets of ccRCC, ICGC-KIRC (the International Cancer Genome Consortium) and GSE29609, as well as a single-cell dataset (GSE156632) and real patient clinical information, and further confirmed the relationship between the senescence-metabolism-related risk score (SeMRS) and ccRCC patient progression. It is worth noting that patients who were classified into different subgroups based on the SeMRS exhibited notable variations in metabolic activity, immune microenvironment, immune cell type transformation, mutant landscape, and drug responsiveness. We also demonstrated that PTGER4, a key gene in SeMRM, regulated ccRCC cell proliferation, lipid levels and the cell cycle in vivo and in vitro. Together, the utilization of SeMRM has the potential to function as a dependable clinical characteristic to increase the accuracy of prognostic assessment for patients diagnosed with ccRCC, thereby facilitating the selection of suitable treatment strategies.

Funder

National Natural Sciences Foundation of China

the Joint Construction Project between Medical Science and Technology Research Project of Henan Province

the Cultivation Fund of Zhengzhou University

Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University

the Training Program for Middle-aged and Young Discipline Leaders of Health of Henan Province

the Training Program of Young and Middle-aged Health Science and Technology Innovation Excellent Youth

Publisher

Springer Science and Business Media LLC

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