title: The mucin MUC4 is a transcriptional and post-transcriptional target of K-ras oncogene in pancreatic cancer. Implication of MAPK/AP-1, NF-κB and RalB signaling pathways.
abstract: The membrane-bound mucinMUC4 is a high molecularweight glycoprotein frequently deregulated in cancer. In pancreatic cancer, one of the most deadly cancers in occidental countries, MUC4 is neo-expressed in the preneoplastic stages and thereafter is involved in cancer cell properties leading to cancer progression and chemoresistance. K-ras oncogene is a small GTPase of the RAS superfamily, highly implicated in cancer. K-ras mutations are considered as an initiating event of pancreatic carcinogenesis and K-ras oncogenic activities are necessary components of cancer progression. However, K-ras remains clinically undruggable. Targeting early downstream K-ras signaling in cancer may thus appear as an interesting strategy and MUC4 regulation by K-ras in pancreatic carcinogenesis remains unknown. Using the Pdx1-Cre; LStopL-K-rasG12D mouse model of pancreatic carcinogenesis, we show that the in vivo early neo-expression of the mucin Muc4 in pancreatic intraepithelial neoplastic lesions (PanINs) induced by mutated K-ras is correlated with the activation of ERK, JNK and NF-κB signaling pathways. In vitro, transfection of constitutively activated K-rasG12V in pancreatic cancer cells led to the transcriptional upregulation of MUC4. This activation was found to be mediated at the transcriptional level by AP-1 and NF-κB transcription factors via MAPK, JNK and NF-κB pathways and at the posttranscriptional level by a mechanism involving the RalB GTPase. Altogether, these results identify MUC4 as a transcriptional and post-transcriptional target of K-ras in pancreatic cancer. This opens avenues in developing new approaches to target the early steps of this deadly cancer.
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Vasseur
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skrypek
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Belinda
authors.initials: B
authors.lastname: Duchêne
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France; Institut de Pathologie, Centre de Biologie Pathologie, Boulevard du Professeur Jules Leclercq, 59037 Lille Cedex, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Renaud
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martínez-Maqueda
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Porchet
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: Inserm, UMR-S 1172, Jean Pierre Aubert Research Center, Team "Mucins, epithelial differentiation and carcinogenesis", 1 rue Polonovski, 59045 Lille cedex, France; Univ Lille Nord de France, 42 rue Paul Duez, F-59000 Lille, France; Centre Hospitalier Régional et Universitaire de Lille, Place de Verdun, 59037 Lille cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jonckheere
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D053612:Janus Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D055264:Mucin-4 / Q000096:biosynthesis* / Q000235:genetics; D020125:Mutation, Missense; D016328:NF-kappa B / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D012323:RNA Processing, Post-Transcriptional; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic; D015854:Up-Regulation; D020725:ral GTP-Binding Proteins / Q000502:physiology
chemical_list: C524658:MUC4 protein, human; C524659:Muc4 protein, mouse; D055264:Mucin-4; D016328:NF-kappa B; D009363:Neoplasm Proteins; C483163:Ralb protein, human; D011993:Recombinant Fusion Proteins; D018808:Transcription Factor AP-1; D053612:Janus Kinases; C535173:RalB protein, mouse; D020725:ral GTP-Binding Proteins
keywords: AP‐1; K-ras; MUC4; Pancreatic cancer; RalB; Transcription