Research Paper Volume 16, Issue 10 pp 9047—9071
Targeting PRKDC activates the efficacy of antitumor immunity while sensitizing to chemotherapy and targeted therapy in liver hepatocellular carcinoma
- 1 The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha 410013, Hunan, China
- 2 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- 3 Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
Received: November 22, 2023 Accepted: April 9, 2024 Published: May 22, 2024
https://doi.org/10.18632/aging.205855How to Cite
Copyright: © 2024 Pan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Liver hepatocellular carcinoma (LIHC) ranks among the malignancies with the highest mortality rates, primarily due to chemoresistance culminating in treatment failure. Despite its impact, predictive models addressing disease progression, tumor microenvironment, and drug sensitivity remain elusive for LIHC patients. Recognizing the significant influence of various programmed cell death (PCD) modes on tumor evolution, this study investigates PCD genes to elucidate their implications on the prognosis and immune landscape of LIHC.
Methods: To develop the classification and model, we employed a total of 17 genes associated with PCD patterns. To collect data, we acquired gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA database, specifically from LIHC patients. Moreover, we obtained spatial transcriptome data and additional bulk datasets from the Gene Expression Omnibus (GEO) database to conduct further analysis. Various experiments were conducted to validate the role of the PCD gene PRKDC in proliferation, migration, invasion, EMT, cell cycle, therapeutic sensitivity, and antitumor immunity.
Results: A novel LIHC classification based on these genes divided patients into two clusters, C1 and C2. The C2 cluster exhibited characteristics indicative of poor prognosis and an immune-activated microenvironment. This group showed greater response potential to immune checkpoint inhibitors, displaying higher levels of certain immune signatures and receptors. A programmed cell death index (PCDI) was constructed using 17 selected PCD genes. This index could effectively predict patient prognosis, with higher PCDI indicating poorer survival rates and a more pro-tumor microenvironment. Immune landscapes revealed varying interactions with PCDI, suggesting therapeutic targets and insights into treatment resistance. Moreover, experiments results suggested that PRKDC can augment the invasive nature and growth of malignant cells and it can serve as a potential target for therapy, offering hope for ameliorating the prognosis of LIHC patients.
Conclusions: The study uncovers the insights of programmed cell death in the prognosis and potential therapeutic interventions. And we found that PRKDC can serve as a target for enhancing the efficacy of antitumor immunity while sensitizing chemotherapy and targeted therapy in liver hepatocellular carcinoma.