E-cadherin-driven interleukin-6 expression promotes autophagy-mediated platinum resistance in ovarian clear cell...

Ovarian clear cell carcinoma (OCCC) is a distinct histological subtype of epithelial ovarian cancer that frequently exhibits chemotherapy resistance and poor outcomes. We investigated the regulatory role of E-cadherin signaling in driving interleukin-6 (IL-6) expression and promoting autophagy-dependent cisplatin resistance. In epithelial-like OCCC cell lines, elevated E-cadherin expression enhanced cisplatin resistance through β-catenin-mediated IL-6 transcription. Proteomic analysis of matched primary and recurrent OCCC specimens revealed upregulation of autophagy signaling in recurrent tumors. Immunoprecipitation confirmed direct interaction between IL-6 and sequestosome-1 (SQSTM1/p62) via its PB1 domain. In cisplatin-refractory patient-derived xenografts, IL-6 blockade significantly inhibited tumor growth. Clinically, in a cohort of 70 OCCC patients, increased serum IL-6 levels correlated with elevated CA125 (p < 0.001), recurrence (p < 0.001), advanced tumor stage (p = 0.014), and worse survival outcomes. High serum IL-6 was independently associated with shorter progression-free survival (p = 0.005). Collectively, these findings identify the E-cadherin/IL-6/autophagy axis as a key mediator of platinum resistance.