MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To control cancer progression, miRNAs became very recently, major targets and tools to inhibit oncogene expression. Inhibiting MUC1 using miRNAs appears thus as an attractive strategy to reduce cancer progression. However, potent miRNAs and associated mechanisms regulating MUC1 expression remain to be identified. To this aim, we undertook to study MUC1 regulation by miRNAs in pancreatic cancer cells and identify those with tumor suppressive activity. MiRNAs potentially targeting the 3'-UTR, the coding region, or the 5'-UTR of MUC1 were selected using an in silico approach. Our in vitro and in vivo experiments indicate that miR-29a and miR-330-5p are strong inhibitors of MUC1 expression in pancreatic cancer cells through direct binding to MUC1 3'-UTR. MUC1 regulation by the other selected miRNAs (miR-183, miR-200a, miR-876-3p and miR-939) was found to be indirect. MiR-29a and miR-330-5p are also deregulated in human pancreatic cancer cell lines and tissues and in pancreatic tissues of Kras(G12D) mice. In vitro, miR-29a and miR-330-5p inhibit cell proliferation, cell migration, cell invasion and sensitize pancreatic cancer cells to gemcitabine. In vivo intra-tumoral injection of these two miRNAs in xenografted pancreatic tumors led to reduced tumor growth. Altogether, we have identified miR-29a and miR-330-5p as two new tumor suppressive miRNAs that inhibit the expression of MUC1 oncogenic mucin in pancreatic cancer cells.
Keywords: Cancer; Chemoresistance; MUC1 mucin; MiRNA; Pancreas.
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