Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells

• Published in: Biochimica et biophysica acta 2015-10, Vol.1853 (10), p.2392-2403
• Main Authors: Tréhoux, Solange, Lahdaoui, Fatima, Delpu, Yannick, Renaud, Florence, Leteurtre, Emmanuelle, Torrisani, Jérôme, Jonckheere, Nicolas, Van Seuningen, Isabelle
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions - genetics; Animals; Cancer; Cell Line, Tumor; Chemoresistance; Genes, Tumor Suppressor; Heterografts; Humans; Life Sciences; Mice; MicroRNAs - biosynthesis; MicroRNAs - genetics; MiRNA; MUC1 mucin; Mucin-1 - biosynthesis; Mucin-1 - genetics; Neoplasm Transplantation; Pancreas; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2015.05.033

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 invitro and invivo 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 KrasG12D 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. •MUC1 is directly repressed by miR-29a and miR-330-5p in PDAC cells.•Expression of miR-29a and miR-330-5p is decreased in human PDAC.•Overexpression of miR-29a and miR-330-5p alters the biological properties of PDAC cell lines.•Overexpression of miR-29a and miR-330-5p sensitizesPDAC cell line to gemcitabine.