Multidrug transporter MRP4/ABCC4 as a key determinant of pancreatic cancer aggressiveness

SAHORES, A.; CAROZZO, A.; MAY, M.; GÓMEZ, N.; DI SIERVI, N.; DE SOUSA SERRO, M.; YANEFF, A.; RODRÍGUEZ-GONZÁLEZ, A.; ABBA, M.; SHAYO, C.; DAVIO, C.

Scientific Reports

nature

Año: 2020 vol. 10

Recent findings show that MRP4 is critical for pancreatic ductal adenocarcinoma (PDAC) cellproliferation. Nevertheless, the significance of MRP4 protein levels and function in PDAC progressionis still unclear. The aim of this study was to determine the role of MRP4 in PDAC tumor aggressiveness.Bioinformatic studies revealed that PDAC samples show higher MRP4 transcript levels comparedto normal adjacent pancreatic tissue and circulating tumor cells express higher levels of MRP4 thanprimary tumors. Also, high levels of MRP4 are typical of high-grade PDAC cell lines and associate withan epithelial-mesenchymal phenotype. Moreover, PDAC patients with high levels of MRP4 depictdysregulation of pathways associated with migration, chemotaxis and cell adhesion. Silencing MRP4in PANC1 cells reduced tumorigenicity and tumor growth and impaired cell migration. Transcriptomicanalysis revealed that MRP4 silencing alters PANC1 gene expression, mainly dysregulating pathwaysrelated to cell-to-cell interactions and focal adhesion. Contrarily, MRP4 overexpression significantlyincreased BxPC-3 growth rate, produced a switch in the expression of EMT markers, and enhancedexperimental metastatic incidence. Altogether, our results indicate that MRP4 is associated with amore aggressive phenotype in PDAC, boosting pancreatic tumorigenesis and metastatic capacity,which could finally determine a fast tumor progression in PDAC patients.