title: miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers in the world with one of the worst outcome. The oncogenic mucin MUC4 has been identified as an actor of pancreatic carcinogenesis as it is involved in many processes regulating pancreatic cancer cell biology. MUC4 is not expressed in healthy pancreas whereas it is expressed very early in pancreatic carcinogenesis. Targeting MUC4 in these early steps may thus appear as a promising strategy to slow-down pancreatic tumorigenesis. miRNA negative regulation of MUC4 could be one mechanism to efficiently downregulate MUC4 gene expression in early pancreatic neoplastic lesions. Using in silico studies, we found two putative binding sites for miR-219-1-3p in the 3'-UTR of MUC4 and showed that miR-219-1-3p expression is downregulated both in PDAC-derived cell lines and human PDAC tissues compared with their normal counterparts. We then showed that miR-219-1-3p negatively regulates MUC4 mucin expression via its direct binding to MUC4 3'-UTR. MiR-219-1-3p overexpression (transient and stable) in pancreatic cancer cell lines induced a decrease of cell proliferation associated with a decrease of cyclin D1 and a decrease of Akt and Erk pathway activation. MiR-219-1-3p overexpression also decreased cell migration. Furthermore, miR-219-1-3p expression was found to be conversely correlated with Muc4 expression in early pancreatic intraepithelial neoplasia lesions of Pdx1-Cre;LSL-Kras(G12D) mice. Most interestingly, in vivo studies showed that miR-219-1-3p injection in xenografted pancreatic tumors in mice decreased both tumor growth and MUC4 mucin expression. Altogether, these results identify miR-219-1-3p as a new negative regulator of MUC4 oncomucin that possesses tumor-suppressor activity in PDAC.
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Lahdaoui
authors.affiliation: 1] Inserm, UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France [2] Université Paul Sabatier, Toulouse, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Delpu
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Vincent
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: Renaud
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Messager
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: B
authors.initials: B
authors.lastname: Duchêne
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: E
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: C
authors.initials: C
authors.lastname: Mariette
authors.affiliation: 1] Inserm, UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France [2] Université Paul Sabatier, Toulouse, France.
authors.forename: J
authors.initials: J
authors.lastname: Torrisani
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: N
authors.initials: N
authors.lastname: Jonckheere
authors.affiliation: 1] Inserm, UMR837, Jean Pierre Aubert Research Center (JPARC), Team 5 'Mucins, epithelial differentiation and carcinogenesis', rue Polonovski, Lille Cedex, France [2] Université Lille Nord de France, Lille, France [3] Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: I
authors.initials: I
authors.lastname: Van Seuningen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D055264:Mucin-4 / Q000096:biosynthesis* / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C578248:MIRN219 microRNA, human; C524658:MUC4 protein, human; D035683:MicroRNAs; D055264:Mucin-4; D051058:Oncogene Protein v-akt