Abstract
Recent findings show that MRP4 is critical for pancreatic ductal adenocarcinoma (PDAC) cell proliferation. Nevertheless, the significance of MRP4 protein levels and function in PDAC progression is 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 compared to normal adjacent pancreatic tissue and circulating tumor cells express higher levels of MRP4 than primary tumors. Also, high levels of MRP4 are typical of high-grade PDAC cell lines and associate with an epithelial-mesenchymal phenotype. Moreover, PDAC patients with high levels of MRP4 depict dysregulation of pathways associated with migration, chemotaxis and cell adhesion. Silencing MRP4 in PANC1 cells reduced tumorigenicity and tumor growth and impaired cell migration. Transcriptomic analysis revealed that MRP4 silencing alters PANC1 gene expression, mainly dysregulating pathways related to cell-to-cell interactions and focal adhesion. Contrarily, MRP4 overexpression significantly increased BxPC-3 growth rate, produced a switch in the expression of EMT markers, and enhanced experimental metastatic incidence. Altogether, our results indicate that MRP4 is associated with a more aggressive phenotype in PDAC, boosting pancreatic tumorigenesis and metastatic capacity, which could finally determine a fast tumor progression in PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, due to its late diagnosis, inherent resistance to treatment and early d issemination[1]
We further explored vimentin and E-cadherin expression in the same panel of pancreatic ductal adenocarcinoma (PDAC) cell lines, as both proteins are associated with the process of epithelial-mesenchymal transition (EMT)
High-grade PDAC cell lines depict EGFR upregulation, which has been associated with advanced stage, metastatic disease, and poor differentiation and survival in pancreatic adenocarcinoma[12,13]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, due to its late diagnosis, inherent resistance to treatment and early d issemination[1]. We described that MRP4 mRNA and protein levels inversely correlate with the degree of differentiation of pancreatic cancer cell lines and that PDAC patients with high expression of MRP4 tend to have a shorter overall survival compared to patients with low MRP4 expression. These findings suggest that MRP4 has tumor promoting functions and that high levels of MRP4 expressed selectively in human pancreatic tumor tissues may contribute to the development of high-risk pancreatic cancer. In PDAC tumor biology and set the basis to further validate this transporter as a potential prognosis biomarker and/or therapeutic target for PDAC
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