SDC2 promotes gemcitabine resistance of bladder cancer via activation of the EGFR-ERK-C-MYC axis mediated epithelial-mesenchymal transition

Gemcitabine resistance represents a major therapeutic obstacle in the treatment of bladder cancer (BLCA). Based on that the transmembrane proteoglycan syndecan-2 (SDC2) expression was markedly upregulated in gemcitabine-resistant BLCA cells, we examined the role of SDC2 in mediating this resistance. Elevated SDC2 levels promoted epithelial-mesenchymal transition (EMT), as suggested by decreased E-cadherin expression and increased levels of vimentin and Snail. Conversely, silencing SDC2 reversed the EMT phenotype, inhibited cell proliferation, invasion, and migration, and restored sensitivity to gemcitabine in vitro, whereas enforced SDC2 overexpression enhanced these malignant characteristics. In vivo, SDC2 knockdown acted synergistically with gemcitabine to significantly suppress tumor growth. Mechanistically, SDC2 activated the EGFR-ERK pathway, leading to the upregulation of the oncogene C-MYC, which in turn drove EMT and conferred chemoresistance. Together, these findings recognize SDC2 as an important regulator of gemcitabine resistance through the EGFR-ERK-C-MYC-EMT axis and underscore it as a potential therapeutic target for overcoming chemotherapy resistance in BLCA.