A novel Senescence-Based prognostic model unveils tumor interactions and drug resistance in colorectal cancer

Yanzhe Yue; Xiangjian She; Wenbo Ding; Shuyu Chen; Qianni Xiao; Bei Pan; Linpeng Zhou; Yujuan Yin; Youyue Li; Shukui Wang; Mu Xu

doi:10.1016/j.intimp.2024.112197

A novel Senescence-Based prognostic model unveils tumor interactions and drug resistance in colorectal cancer

Int Immunopharmacol. 2024 May 10:134:112197. doi: 10.1016/j.intimp.2024.112197. Online ahead of print.

Authors

Yanzhe Yue¹, Xiangjian She¹, Wenbo Ding¹, Shuyu Chen¹, Qianni Xiao¹, Bei Pan², Linpeng Zhou¹, Yujuan Yin², Youyue Li², Shukui Wang³, Mu Xu⁴

Affiliations

¹ General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 211166, Nanjing, Jiangsu, China; School of Basic-Medicine and Clinical Pharmacy, Nanjing First Hospital, China Pharmaceutical University, 211198, Nanjing, Jiangsu, China.
² General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 211166, Nanjing, Jiangsu, China.
³ General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 211166, Nanjing, Jiangsu, China; School of Basic-Medicine and Clinical Pharmacy, Nanjing First Hospital, China Pharmaceutical University, 211198, Nanjing, Jiangsu, China; Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, 211166, Nanjing, Jiangsu, China. Electronic address: sk_wang@njmu.edu.
⁴ Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, 211166, Nanjing, China. Electronic address: xumu123456@hotmail.com.

PMID: 38733826
DOI: 10.1016/j.intimp.2024.112197

Abstract

Background: In China, CRC incidence is escalating. The main hurdles are heterogeneity and drug resistance. This research delves into cellular senescence in CRC, aiming to devise a prognostic model and pinpoint mechanisms impacting drug resistance.

Methods: Mendelian randomization (MR) analysis confirmed the association between CRC and cellular aging. The Cancer Genome Atlas (TCGA)-CRC data served as the training set, with GSE38832 and GSE39582 as validation sets. Various bioinformatics methods were employed to construct and validate a risk model. CRC cells with NADPH Oxidase 4 (NOX4) knockout were generated using CRISPR-Cas9 technology. Protein blotting and colony formation assays elucidated the role of NOX4 in CRC cell aging and drug resistance.

Results: A prognostic model, derived from dataset analysis, uncovered a link between high-risk groups and cancer progression. Notable differences in the tumor microenvironment were observed between risk groups. Finally, NOX4 was found to be linked with aging and drug resistance in CRC.

Conclusion: This research presents a novel senescence-based CRC prognosis model. It identifies NOX4's role in CRC drug resistance, suggesting it is a potential treatment target.

Keywords: Cellular Senescence; Colorectal Cancer (CRC); Drug Resistance; NOX4; Tumor Microenvironment (TME).