Integrative Analysis Combining Machine Learning and Functional Experiments Uncovers ISG15 As a Key Determinant of...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cisplatin resistance is a significant challenge in treating advanced gastric cancer (GC).
• Interferon-stimulated genes (ISGs) are implicated in cellular responses to chemotherapy.
• Identifying key regulators of chemoresistance is crucial for developing effective therapies.

Purpose of the Study:

• To identify molecular determinants of cisplatin resistance in GC, focusing on ISGs.
• To investigate the functional role of interferon-stimulated gene 15 (ISG15) in mediating chemoresistance.

Main Methods:

• Transcriptomic profiling and machine learning (LASSO, SVM-RFE, RF) to identify candidate genes.
• Bioinformatic and experimental validation in GC cell lines (AGS, AGS/DDP).
• siRNA-mediated knockdown to assess ISG15 function in cell viability, colony formation, migration, and cisplatin sensitivity.

Main Results:

• ISG15, OAS2, IFI44, and IFIT3 were identified as central hub genes.
• ISG15 was significantly upregulated in cisplatin-resistant GC cells and induced by cisplatin.
• ISG15 knockdown reduced cell viability, migration, and enhanced cisplatin sensitivity.

Conclusions:

• ISG15 is a key regulator of cisplatin resistance and tumor progression in GC.
• Machine learning combined with functional validation effectively identifies therapeutic targets.
• ISG15 represents a potential therapeutic target for overcoming cisplatin resistance in gastric cancer.