Cisplatin-resistant germ cell tumor models: An exploration of the epithelial-mesenchymal transition regulator SLUG

Germ cell tumors (GCTs) constitute diverse neoplasms arising in the gonads or extragonadal locations. Testicular GCTs (TGCTs) are the predominant solid tumors in adolescents and young men. Despite cisplatin serving as the primary therapeutic intervention for TGCTs, 10-20% of patients with advanced disease demonstrate resistance to cisplatin-based chemotherapy, and epithelial-mesenchymal transition (EMT) is a potential contributor to this resistance. EMT is regulated by various factors, including the snail family transcriptional repressor 2 (SLUG) transcriptional factor, and, to the best of our knowledge, remains unexplored within TGCTs. Therefore, the present study investigated the EMT transcription factor SLUG in TGCTs. In silico analyses were performed to investigate the expression of EMT markers in TGCTs. In addition, a cisplatin-resistant model for TGCTs was developed using the NTERA-2 cell line, and a mouse model was also established. Subsequently, EMT was assessed both in vitro and in vivo within the cisplatin-resistant models using quantitative PCR and western blot analyses. The results of the in silico analysis showed that the different histologies exhibited distinct expression profiles for EMT markers. Seminomas exhibited a lower expression of EMT markers, whereas embryonal carcinomas and mixed GCT demonstrated high expression. Notably, patients with lower SLUG expression had longer median progression-free survival (46.4 months vs. 28.0 months, P=0.022). In the in vitro analysis, EMT-associated genes [fibronectin; vimentin (VIM); actin, alpha 2, smooth muscle; collagen type I alpha 1; transforming growth factor-beta 1; and SLUG] were upregulated in the cisplatin-resistant NTERA-2 (NTERA-2R) cell line after 72 h of cisplatin treatment. Consistent with this finding, the NTERA-2R mouse model demonstrated a significant upregulation in the expression levels of VIM and SLUG. In conclusion, the present findings suggested that SLUG may serve a crucial role in connecting EMT with the development of cisplatin resistance, and targeting SLUG may be a putative therapeutic strategy to mitigate cisplatin resistance.