EDC4 enhances multi-drug chemosensitivity in pancreatic cancer via GR50-based profiling.

Abstract

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.