PDZK1 inhibits MRP2-mediated oxaliplatin chemosensitivity in hepatocellular carcinoma

Recurrence after oxaliplatin chemotherapy is a major challenge in the treatment of advanced hepatocellular carcinoma patients. Differential expression gene analysis and Kaplan-Meier curves were screened biomarkers associated with OXA-treated recurrence in GSE51951, TCGA-LIHC, and Chinese Liver Cancer Atlas databases. We retrospectively collected 39 cases of HCC treated with platinum based drugs at the First Hospital of Shanxi Medical University. Immunohistochemistry was used to analyze the relationship between PDZK1 expression and patient recurrence of HCC. Cell model and subcutaneous transplant tumor model of HCC were established to detect the cell growth ability treated with OXA. Gene Set Enrichment Analysis analysis identified signaling pathways associated with high PDZK1. Co-Immunoprecipitation and immunofluorescence experiments were used to explore the potential interaction between PDZK1 and MRP2. We identified that high expression of PDZK1 was associated with OXA resistance and poor prognosis in HCC. PDZK1 promoted the cell viability, migration, and invasion of HCC after OXA treatment in vitro and vivo. MRP2-mediated ABC transporters pathway and bile acid metabolism were significantly activated in the PDZK1 overexpression group of HCC. PDZK1 interacted and co-localized with the carboxyl terminal PDZ binding motif of MRP2. Clinical specimen analysis have shown a positive correlation between the protein levels of PDZK1 and MRP2. Our study identified PDZK1 as a novel biomarker significantly associated with OXA chemosensitivity in HCC. Mechanistically, PDZK1 promoted the OXA sensitivity of HCC by activating the MRP2-mediated signaling pathway.