The Transcription Factor SOX5 as a Potential Marker of Resistance to Chemotherapy in Gastric Cancer Cell Lines

Chemoresistance is one of the major barriers to effective treatment in gastric cancer (GC), contributing to disease progression and poor patient survival. SRY-box transcription factor 5 (SOX5) has been associated with aggressive cancer phenotypes in several malignancies; however, its relationship with chemoresistance in GC has yet to be fully characterized. This study investigated whether SOX5 expression is associated with molecular features linked to aggressive GC phenotypes, including multi-drug resistance proteins, cancer stem cell (CSC) antigens, epithelial–mesenchymal transition (EMT) markers, and proteins involved in drug efflux and DNA repair. SOX5 expression was evaluated in AGS and MKN-45 GC cell lines using Western blotting, real-time quantitative PCR, and immunofluorescence. Markers associated with EMT (Snail1, ZEB1, and E-cadherin), CSC phenotypes (CD44 and CD133), DNA repair (XRCC1 and ERCC2), and drug efflux (ABCB1) were analyzed. Cellular sensitivity to 5-fluorouracil (5-FU) and oxaliplatin (Ox) was assessed using an MTT-based viability assay. In addition, publicly available GC datasets were analyzed to evaluate the association between SOX5 expression and overall survival. AGS cells exhibited significantly higher SOX5 expression at both the mRNA and protein levels compared with MKN-45 cells. High SOX5 expression was associated with increased expression of the transcription factors Snail1 and ZEB1, which are associated with EMT, leading to decreased E-cadherin expression. Furthermore, SOX5 expression was associated with increased expression of CD133, the DNA repair genes XRCC1 and ERCC2, and ABCB1 transcripts. Consistent with these molecular findings, AGS cells exhibited greater viability following exposure to 5-FU and Ox, either alone or in combination, suggesting reduced sensitivity to these agents. Furthermore, high SOX5 expression was associated with poorer overall survival across independent GC patient cohorts. Overall, these findings suggest SOX5 as a potential biomarker associated with an aggressive molecular phenotype characterized by EMT activation, enhanced DNA repair capacity, stemness-associated features, and reduced sensitivity to FOLFOX-based chemotherapy. Future mechanistic studies are warranted to establish whether SOX5 directly drives these processes.