Transcriptomic data integration and analysis revealing potential mechanisms of doxorubicin resistance in...

Chondrosarcoma is a type of bone cancer that originates from cartilage cells. In clinical practice, surgical resection is the primary treatment for chondrosarcoma, but chemotherapy becomes essential for patients with metastasis or tumors in surgically inaccessible sites. However, drug resistance often leads to treatment failure. Tumor microenvironment proteins modulate intercellular communication, contributing to drug resistance. Doxorubicin (Dox) is a common chemotherapeutic agent. The present study aimed to establish Dox-resistant chondrosarcoma cells and compare their secretome with parental cells using antibody arrays. Results showed significantly heightened secretion of hepatocyte growth factor (HGF). Knockdown of both HGF and its receptor MET increased Dox sensitivity in chondrosarcoma cells. Treatment of chondrosarcoma cells with conditioned media (CM) from cells secreting high levels of HGF resulted in MET activation. Additionally, the expression levels of HGF and MET were significantly elevated in chondrosarcoma tissues compared to normal cartilage tissues, as confirmed by analysis of GEO database. RNA sequencing and Gene Set Enrichment Analysis (GSEA) elucidated the mechanism involving HGF. Additionally, genes with log fold change > 1 underwent bioinformatics analysis using the ShinyGO web server. The results from both GSEA and ShinyGO analyses corroborate each other, indicating the significance of HGF in cellular signal transduction, regulation of cell motility, developmental processes, immune-inflammatory responses, and functions related to blood and neural systems. In summary, highly secreted HGF can activate signaling pathways through its receptor MET, particularly Ras and Akt activation, enhancing drug resistance in chondrosarcoma cells. The present study may guide the development of novel therapeutic strategies targeting HGF, ultimately improving treatment outcomes and prognosis for malignant chondrosarcoma patients.