Identification of a chemoresistance-related prognostic gene signature by comprehensive analysis and experimental validation in pancreatic cancer

Frontiers in Oncology

Oncology

Junliang Chen¹  Zhiyuan Wu¹  Wenjun Li¹  Zhihao Liu¹  Xiaodong Tan¹ 

[1] Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China;

关键词: pancreatic cancer;    chemoresistance;    gemcitabine;    prognosis;    immunotherapy;    tumor microenvironment;    tumor mutation burden;   

DOI  :  10.3389/fonc.2023.1132424

 received in 2022-12-30, accepted in 2023-05-02,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundChemoresistance is a major hurdle to improving the prognosis of pancreatic cancer (PC). This study aimed to identify key genes regulating chemoresistance and develop a chemoresistance-related gene signature for prognosis prediction.MethodsA total of 30 PC cell lines were subtyped according to gemcitabine sensitivity data from the Cancer Therapeutics Response Portal (CTRP v2). Differentially expressed genes (DEGs) between gemcitabine-resistant and gemcitabine-sensitive cells were subsequently identified. These upregulated DEGs associated with prognostic values were incorporated to build a LASSO Cox risk model for The Cancer Genome Atlas (TCGA) cohort. Four datasets (GSE28735, GSE62452, GSE85916, and GSE102238) from the Gene Expression Omnibus (GEO) were used as an external validation cohort. Then, a nomogram was developed based on independent prognostic factors. The responses to multiple anti-PC chemotherapeutics were estimated by the “oncoPredict” method. Tumor mutation burden (TMB) was calculated using the “TCGAbiolinks” package. Analysis of the tumor microenvironment (TME) was performed using the “IOBR” package, while the TIDE and “easier” algorithms were employed to estimate immunotherapy efficacy. Finally, RT-qPCR, Western blot and CCK-8 assays were conducted to validate the expression and functions of ALDH3B1 and NCEH1.ResultsA five-gene signature and a predictive nomogram were developed from six prognostic DEGs, including EGFR, MSLN, ERAP2, ALDH3B1, and NCEH1. Bulk and single-cell RNA sequencing analyses indicated that all five genes were highly expressed in tumor samples. This gene signature was not only an independent prognostic factor but also a biomarker forecasting chemoresistance, TMB, and immune cells. In vitro experiments suggested that ALDH3B1 and NCEH1 were involved in PC progression and gemcitabine chemoresistance.ConclusionThis chemoresistance-related gene signature links prognosis with chemoresistance, TMB, and immune features. ALDH3B1 and NCEH1 are two promising targets for treating PC.

【 授权许可】

Unknown   
Copyright © 2023 Chen, Liu, Wu, Li and Tan