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EDC4 enhances multi-drug chemosensitivity in pancreatic cancer via GR50-based profiling
Cheng Qin1, Tianyu Li1, Bangbo Zhao1
1Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Background:
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with drug resistance significantly impeding effective chemotherapy. The clinical importance of key genes in PDAC chemoresistance remains unclear.
Methods:
Cytotoxicity assays were conducted on eight PDAC cell lines treated with gemcitabine, albumin paclitaxel, irinotecan, 5-FU, and cis-platinum. Based on GR50 values, cell lines were categorized as chemosensitive (CS) or chemoresistant (CR). RNA-seq data from the Cancer Cell Line Encyclopedia were analyzed for differential gene expression. Various statistical methods, including univariate Cox, LASSO, random forest, and multivariate Cox regression, were employed to construct a risk signature. This model's effectiveness was validated using time-dependent ROC curves and Kaplan-Meier survival analysis in TCGA and GSE57495 + GSE28735 combined datasets. Downstream molecules of core genes were explored, and the core gene's function was validated through in vivo and in vitro experiments.
Results:
Drug resistance profiles were established based on GR50 values. EDC4 and USP20 were identified as key genes in the risk signature. qRT-PCR validated core gene expressions in PDAC cell lines. EDC4 was selected for further analysis due to its highest correlation coefficient in the multivariate Cox regression model. EDC4 knockdown increased proliferation and chemoresistance in MIA PaCa-2 cells, while overexpression inhibited these traits in AsPC-1 cells. MATN3 and SGCE were identified as downstream targets of EDC4. Immunohistochemistry of tissue microarrays confirmed that low EDC4 levels were associated with poor prognosis in PDAC, highlighting its potential as a therapeutic target.
Conclusion:
PDAC cell lines exhibit distinct chemoresistance capabilities. EDC4 and its downstream targets MATN3 and SGCE play significant roles in PDAC multidrug chemoresistance, providing novel insights for treatment.
Insights
Pancreatic cancer drug resistance is a major challenge. Researchers identified EDC4 as a key gene influencing chemoresistance, offering new therapeutic targets for pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with significant challenges in chemotherapy due to drug resistance.
- The specific genes contributing to PDAC chemoresistance require further clinical investigation.
Purpose of the Study:
- To investigate the role of key genes in pancreatic cancer chemoresistance.
- To develop a predictive risk signature for PDAC chemoresistance.
- To identify potential therapeutic targets for improving PDAC treatment outcomes.
Main Methods:
- Cytotoxicity assays were performed on eight PDAC cell lines against various chemotherapeutic agents.
- RNA-sequencing data were analyzed to identify differentially expressed genes.
- Statistical models including Cox regression and random forest were used to construct a risk signature.
- Gene function was validated through in vitro (gene knockdown/overexpression) and in vivo experiments.
Main Results:
- Distinct chemoresistance profiles were observed across PDAC cell lines.
- EDC4 and USP20 were identified as key genes in a novel risk signature.
- EDC4 knockdown increased proliferation and chemoresistance, while overexpression inhibited these traits.
- Low EDC4 expression correlated with poor prognosis in PDAC patients.
Conclusions:
- EDC4 and its downstream targets (MATN3, SGCE) are significantly involved in PDAC multidrug chemoresistance.
- EDC4 represents a potential therapeutic target for enhancing pancreatic cancer treatment.
- These findings offer novel insights into overcoming chemoresistance in PDAC.
