164 results on '"Jonckheere, Nicolas"'
Search Results
2. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting
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Jonckheere, Nicolas, Vasseur, Romain, and Van Seuningen, Isabelle
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- 2017
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3. Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model
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Siebert, Matthieu, Ribeiro-Parenti, Lara, Nguyen, Nicholas D., Hourseau, Muriel, Duchêne, Belinda, Humbert, Lydie, Jonckheere, Nicolas, Nuel, Grégory, Chevallier, Jean-Marc, Duboc, Henri, Rainteau, Dominique, Msika, Simon, Kapel, Nathalie, Couvelard, Anne, Bado, André, and Le Gall, Maude
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- 2020
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4. A novel anti-galectin-9 immunotherapy limits the early progression of pancreatic neoplastic lesions in transgenic mice.
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Quilbe, Alexandre, Mustapha, Rami, Duchêne, Belinda, Kumar, Abhishek, Werkmeister, Elisabeth, Leteurtre, Emmanuelle, Moralès, Olivier, Jonckheere, Nicolas, Van Seuningen, Isabelle, and Delhem, Nadira
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PANCREATIC intraepithelial neoplasia ,PANCREATIC tumors ,TRANSGENIC mice ,REGULATORY T cells ,IMMUNE checkpoint inhibitors ,PRECANCEROUS conditions ,T cells - Abstract
Background: Pancreatic adenocarcinoma (PDAC) is a devastating disease with an urgent need for therapeutic innovation. Immune checkpoint inhibition has shown promise in a variety of solid tumors, but most clinical trials have failed to demonstrate clinical efficacy in PDAC. This low efficacy is partly explained by a highly immunosuppressive microenvironment, which dampens anti-tumor immunity through the recruitment or induction of immunosuppressive cells, particularly regulatory T cells (Tregs). In this context, our laboratory has developed a novel immunotherapeutic strategy aimed at inhibiting the suppressive activity of Tregs, based on a patented (EP3152234B1) monoclonal antibody (mAb) targeting galectin-9 (LGALS9). Materials and methods: CD4+ conventional T cells (TCD4 or Tconv), Treg ratio, and LGALS9 expression were analyzed by immunohistochemistry (IHC) and cytometry in blood and pancreas of K-rasLSL.G12D/+;Pdx-1-Cre (KC) and KrasWildType (WT);Pdx1-Cre (WT) mice aged 4-13 months. Pancreatic intraepithelial neoplasm (PanIN) progression and grade were quantified using FIJI software and validated by pathologists. The anti-galectin-9 mAb was validated for its use in mice on isolated murine C57BL/6 Treg by immunofluorescence staining and cytometry. Its specificity and functionality were validated in proliferation assays on rLGALS9-immunosuppressed murine Tconv and in suppression assays between murine Treg and Tconv. Finally, 2-month-old KC mice were treated with anti-LGALS9 and compared to WT mice for peripheral and infiltrating TCD4, Treg, and PanIN progression. Results: IHC and cytometry revealed a significant increase in LGALS9 expression and Treg levels in the blood and pancreas of KC mice proportional to the stages of precancerous lesions. Although present in WT mice, LGALS9 is expressed at a basal level with low and restricted expression that increases slightly over time, while Treg cells are few in number in their circulation and even absent from the pancreas over time. Using our anti-LGALS9 mAb in mice, it is shown that (i) murine Treg express LGALS9, (ii) the mAb could target and inhibit recombinant murine LGALS9, and (iii) neutralize murine Treg suppressive activity. Finally, the anti-LGALS9 mAb in KC mice reduced (i) LGALS9 expression in pancreatic cancer cells, (ii) the Treg ratio, and (iii) the total surface area and grade of PanIN. Conclusion: We demonstrate for the first time that an anti-LGALS9 antibody, by specifically targeting endogenous LGALS9 tumor and exogenous LGALS9 produced by Treg, was able to limit the progression of pancreatic neoplastic lesions in mice, opening up new prospects for its use as an immunotherapeutic tool in PDAC. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Metabolism of pancreatic neuroendocrine tumors: what can omics tell us?
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Jannin, Arnaud, Dessein, Anne-Frédérique, Do Cao, Christine, Vantyghem, Marie-Christine, Chevalier, Benjamin, Van Seuningen, Isabelle, Jonckheere, Nicolas, and Coppin, Lucie
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PANCREATIC tumors ,NEUROENDOCRINE tumors ,AMINO acid metabolism ,KREBS cycle ,GENE expression profiling ,METABOLISM - Abstract
Introduction: Reprogramming of cellular metabolism is now a hallmark of tumorigenesis. In recent years, research on pancreatic neuroendocrine tumors (pNETs) has focused on genetic and epigenetic modifications and related signaling pathways, but few studies have been devoted to characterizing the metabolic profile of these tumors. In this review, we thoroughly investigate the metabolic pathways in pNETs by analyzing the transcriptomic and metabolomic data available in the literature. Methodology: We retrieved and downloaded gene expression profiles from all publicly available gene set enrichments (GSE43797, GSE73338, and GSE117851) to compare the differences in expressed genes based on both the stage and MEN1 mutational status. In addition, we conducted a systematic review of metabolomic data in NETs. Results: By combining transcriptomic and metabolomic approaches, we have identified a distinctive metabolism in pNETs compared with controls without pNETs. Our analysis showed dysregulations in the one-carbon, glutathione, and polyamine metabolisms, fatty acid biosynthesis, and branched-chain amino acid catabolism, which supply the tricarboxylic acid cycle. These targets are implicated in pNET cell proliferation and metastasis and could also have a prognostic impact. When analyzing the profiles of patients with or without metastasis, or with or without MEN1 mutation, we observed only a few differences due to the scarcity of published clinical data in the existing research. Consequently, further studies are now necessary to validate our data and investigate these potential targets as biomarkers or therapeutic solutions, with a specific focus on pNETs. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Cryosectioning the intestinal crypt-villus axis: An ex vivo method to study the dynamics of epigenetic modifications from stem cells to differentiated cells
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Vincent, Audrey, Kazmierczak, Catherine, Duchêne, Belinda, Jonckheere, Nicolas, Leteurtre, Emmanuelle, and Van Seuningen, Isabelle
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- 2015
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7. Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large-scale genomic databases: MUC4/MUC16/MUC20 signature is associated with poor survival in human carcinomas
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Jonckheere, Nicolas and Van Seuningen, Isabelle
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- 2018
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8. Helicobacter pylori urease and flagellin alter mucin gene expression in human gastric cancer cells
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Perrais, Michaël, Rousseaux, Christel, Ducourouble, Marie-Paule, Courcol, René, Vincent, Pascal, Jonckheere, Nicolas, and Van Seuningen, Isabelle
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- 2014
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9. Overexpression of chemokine receptor CXCR2 and ligand CXCL7 in liver metastases from colon cancer is correlated to shorter disease-free and overall survival
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Desurmont, Thibault, Skrypek, Nicolas, Duhamel, Alain, Jonckheere, Nicolas, Millet, Guillaume, Leteurtre, Emmanuelle, Gosset, Pierre, Duchene, Belinda, Ramdane, Nassima, Hebbar, Mohamed, Van Seuningen, Isabelle, Pruvot, François-René, Huet, Guillemette, and Truant, Stéphanie
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- 2015
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10. Conséquences du bypass gastrique à une anastomose sur la muqueuse oeso-gastrique dans un modèle préclinique murin
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Siebert, Matthieu, Ribeiro-Parenti, Lara, Nguyen, Nicholas, Hourseau, Muriel, Duchêne, Belinda, Humbert, Lydie, Jonckheere, Nicolas, Nuel, Grégory, Chevallier, Jean-Marc, Duboc, Henri, Rainteau, Dominique, Msika, Simon, Kapel, Nathalie, Couvelard, Anne, Bado, André, Le Gall, Maude, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomopathologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Center for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Universitat Pompeu Fabra [Barcelona] (UPF), Laboratoire de Probabilités, Statistiques et Modélisations (LPSM (UMR_8001)), Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Louis Mourrier, Microorganismes, Molécules Bioactives et Physiopathologie Intestinale (LBM-E4), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ecosystème intestinal, probiotiques, antibiotiques (EA 4065), Université Paris Descartes - Paris 5 (UPD5), Service d'Anatomo-Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lille Neurosciences & Cognition - U 1172 (LilNCog), and Laboratoire de Probabilités, Statistique et Modélisation (LPSM (UMR_8001))
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[SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
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- 2020
11. TRPM7 Modulates Human Pancreatic Stellate Cell Activation.
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Auwercx, Julie, Kischel, Philippe, Lefebvre, Thibaut, Jonckheere, Nicolas, Vanlaeys, Alison, Guénin, Stéphanie, Radoslavova, Silviya, Van Seuningen, Isabelle, Ouadid-Ahidouch, Halima, Kocher, Hemant M., Dhennin-Duthille, Isabelle, and Gautier, Mathieu
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PANCREATIC duct ,LIVER cells ,FIBROBLASTS ,PANCREATIC diseases ,PI3K/AKT pathway ,CELL cycle - Abstract
Pancreatic diseases, such as pancreatitis or pancreatic ductal adenocarcinoma, are characterized by the presence of activated pancreatic stellate cells (PSCs). These cells represent key actors in the tumor stroma, as they actively participate in disease development and progression: reprograming these PSCs into a quiescent phenotype has even been proposed as a promising strategy for restoring the hallmarks of a healthy pancreas. Since TRPM7 channels have been shown to regulate hepatic stellate cells proliferation and survival, we aimed to study the role of these magnesium channels in PSC activation and proliferation. PS-1 cells (isolated from a healthy pancreas) were used as a model of healthy PSCs: quiescence or activation were induced using all-trans retinoic acid or conditioned media of pancreatic cancer cells, respectively. The role of TRPM7 was studied by RNA silencing or by pharmacological inhibition. TRPM7 expression was found to be correlated with the activation status of PS-1 cells. TRPM7 expression was able to regulate proliferation through modulation of cell cycle regulators and most importantly p53, via the PI3K/Akt pathway, in a magnesium-dependent manner. Finally, the analysis of TCGA database showed the overexpression of TRPM7 in cancer-associated fibroblasts. Taken together, we provide strong evidences that TRPM7 can be considered as a marker of activated PSCs. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Analysis of mPygo2 mutant mice suggests a requirement for mesenchymal Wnt signaling in pancreatic growth and differentiation
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Jonckheere, Nicolas, Mayes, Erin, Shih, Hung-Ping, Li, Boan, Lioubinski, Oleg, Dai, Xing, and Sander, Maike
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Stem cells -- Growth ,Company growth ,Biological sciences - Abstract
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.03.014 Byline: Nicolas Jonckheere (a), Erin Mayes (a), Hung-Ping Shih (a), Boan Li (b), Oleg Lioubinski (a), Xing Dai (b), Maike Sander (a) Keywords: Pygopus; Wnt; Pancreas development; Mesenchyme; Islet; Endocrine; Proliferation; Differentiation; Mouse Abstract: Pygopus has recently been identified in Drosophila as an essential component of the nuclear complex required for canonical Wnt signaling. Here, we have investigated the role of the mammalian pygopus ortholog, mPygo2, in pancreas development. We show that a null mutation of mPygo2 in mice causes pancreas hypoplasia due to decreased progenitor cell proliferation after embryonic day (e) 12.5. During the same time window, mPygo2-deficient embryos begin to display a reduction in endocrine progenitors and consequently a decrease in islet endocrine cell mass. Consistent with its function after e12.5, late-developing endocrine cell types, such as beta, delta and PP cells, are specifically reduced, while the earlier-forming alpha cells develop normally. We find canonical Wnt signaling to be predominantly active in the mesenchyme at the time when mPygo2 is required and demonstrate the dependence of Wnt signal transduction on mPygo2. Furthermore, conditional deletion of mPygo2.sup.flox allele in the pancreatic epithelium does not phenocopy the defects in mPygo2-null mutants. Since mPygo2 is expressed in the pancreatic mesenchyme and the role of the mesenchyme in epithelial progenitor cell expansion is well documented, our findings suggest an indirect role for mPygo2 in epithelial growth and differentiation through regulation of mesenchymal signals. Together, our data suggest a previously unappreciated role for mesenchymal Wnt signaling in regulating pancreatic organ growth and cell differentiation. Author Affiliation: (a) Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697-2300, USA (b) Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697-1700, USA Article History: Received 23 October 2007; Revised 10 February 2008; Accepted 3 March 2008
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- 2008
13. Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer
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Neve, Bernadette, Jonckheere, Nicolas, Vincent, Audrey, Van Seuningen, Isabelle, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Jonckheere, Nicolas
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[SDV.CAN] Life Sciences [q-bio]/Cancer ,lncRNA Urothelial Cancer Associated 1 (UCA1) ,[SDV]Life Sciences [q-bio] ,competing endogenous RNAs (ceRNA) ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Review ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,colorectal cancer (CRC) ,long non-coding RNA (lncRNA) ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience; Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells.
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- 2018
14. A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-β in pancreatic carcinogenesis
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Jonckheere, Nicolas, Perrais, Michaël, Mariette, Christophe, Batra, Surinder K, Aubert, Jean-Pierre, Pigny, Pascal, and Van Seuningen, Isabelle
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- 2004
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15. Inositol (1,4,5)-Trisphosphate Receptors in Invasive Breast Cancer: A New Prognostic Tool?
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Foulon, Arthur, Rybarczyk, Pierre, Jonckheere, Nicolas, Brabencova, Eva, Sevestre, Henri, Ouadid-Ahidouch, Halima, and Rodat-Despoix, Lise
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CANCER invasiveness ,PROGRESSION-free survival ,PROGNOSTIC tests ,BREAST cancer ,INOSITOL ,HORMONE receptors ,RYANODINE receptors ,CANCER cells - Abstract
Simple Summary: The inositol-trisphosphate receptor (IP
3 R) is a key player in physiological and pathological intracellular calcium signaling. The objective of the present study was to assess the putative value of the three IP3 R subtypes as prognostic biomarkers in breast cancer. We found that IP3 R3 is the most strongly expressed subtype in breast cancer tissue. Furthermore, IP3 R3 and IP3 R1 are significantly more expressed in invasive breast cancer tissue than in non-tumor tissue. In contrast to IP3 R1 and IP3 R2, the expression of IP3 R3 was positively correlated with prognostic factors including tumor size, regional node invasion, histologic grade, proliferation index, and hormonal status. By analyzing public databases, we found that the expression of all IP3 R subtypes is significantly correlated with the overall survival and disease-free survival of patients with breast cancer. We conclude that relative to the other two IP3 R subtypes, IP3 R3 expression is upregulated in breast cancer and is correlated with prognostic factors. We strongly believe that our results will open up new perspectives with regard to the link between IP3 Rs and breast cancer aggressiveness. Breast cancer is the leading cause of cancer death among women in worldwide and France. The disease prognosis and treatment differ from one breast cancer subtype to another, and the disease outcome depends on many prognostic factors. Deregulation of ion flux (especially Ca2+ flux) is involved in many pathophysiology processes, including carcinogenesis. Inside the cell, the inositol-trisphosphate receptor (IP3 R) is a major player in the regulation of the Ca2+ flux from the endoplasmic reticulum to the cytoplasm. The IP3 Rs (and particularly the IP3 R3 subtype) are known to be involved in proliferation, migration, and invasion processes in breast cancer cell lines. The objective of the present study was to evaluate the potential value of IP3 Rs as prognostic biomarkers in breast cancer. We found that expression levels of IP3 R3 and IP3 R1 (but not IP3 R2) were significantly higher in invasive breast cancer of no special type than in non-tumor tissue from the same patient. However, the IP3 R3 subtype was expressed more strongly than the IP3 R1 and IP3 R2 subtypes. Furthermore, the expression of IP3 R3 (but not of IP3 R1 or IP3 R2) was positively correlated with prognostic factors such as tumor size, regional node invasion, histologic grade, proliferation index, and hormone receptor status. In an analysis of public databases, we found that all IP3 Rs types are significantly associated with overall survival and progression-free survival in patients with breast cancer. We conclude that relative to the other two IP3 R subtypes, IP3 R3 expression is upregulated in breast cancer and is correlated with prognostic factors. [ABSTRACT FROM AUTHOR]- Published
- 2022
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16. The mouse Muc5b mucin gene is transcriptionally regulated by thyroid transcription factor-1 (TTF-1) and GATA-6 transcription factors
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Jonckheere, Nicolas, Velghe, Amélie, Ducourouble, Marie-Paule, Copin, Marie-Christine, Renes, Ingrid B., and Van Seuningen, Isabelle
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- 2011
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17. MOESM5 of Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large-scale genomic databases: MUC4/MUC16/MUC20 signature is associated with poor survival in human carcinomas
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Jonckheere, Nicolas and Seuningen, Isabelle Van
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sense organs - Abstract
Additional file 5: Figure S4. Correlation of MUC4 expression and copy numbers of genes correlated with MUC4. The top genes were defined as genes harboring Pearsonâ s correlation higher than 0.5 with MUC4 expression. MUC4 mRNA expression and log2 copy number of ADGRF1, LCN2, MUC20, C1ORF116, STEAP4, SCEL, MUC16 were extracted using ( https://portals.broadinstitute.org/ccle ).
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- 2018
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18. Analyse des divergences économiques au sein de la zone euro: conséquences pour le futur de la zone monétaire
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Jonckheere, Nicolas, UCL - Faculté des sciences économiques, sociales, politiques et de communication, and Pensieroso, Luca
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politique monétaire ,zone euro ,divergences - Abstract
Le but de ce mémoire est de répondre à la question suivante: les divergences économiques au sein de la zone euro sont-elles telles qu'une séparation de la zone euro est une meilleure issue que le maintien de l'euro? Afin d'y répondre, nous faisons le point sur les bénéfices procurés par la zone euro ainsi que l'évolution de la gouvernance au sein de celle-ci dans un premier temps. Ensuite nous analysons les divergences au sein de la zone à l'aide d'une forme générale de la théorie de la zone monétaire optimale. Dans la troisième partie nous vérifions l'incidence de ces divergences sur l'efficacité de la politique monétaire. Enfin nous formulons nos recommandations pour garantir le futur de la zone euro. Master [120] en sciences économiques, orientation générale, Université catholique de Louvain, 2017
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- 2017
19. The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2
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Skrypek, Nicolas, Vasseur, Romain, Audrey Vincent, Duchene, Belinda, Seuningen, Isabelle, Jonckheere, Nicolas, Jonckheere, Nicolas, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
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Male ,Antimetabolites, Antineoplastic ,endocrine system diseases ,Receptor, ErbB-2 ,pancreatic cancer ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mice, SCID ,Irinotecan ,Transfection ,Deoxycytidine ,ErbB2 ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Databases, Genetic ,Animals ,Humans ,RNA, Messenger ,neoplasms ,Cell Death ,gemcitabine ,Membrane Transport Proteins ,chemoresistance ,Xenograft Model Antitumor Assays ,Multidrug Resistance-Associated Protein 2 ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,FOLFIRINOX ,Drug Resistance, Neoplasm ,Gene Knockdown Techniques ,Camptothecin ,RNA Interference ,Multidrug Resistance-Associated Proteins ,Signal Transduction ,Research Paper - Abstract
International audience; Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers because of a lack of early diagnostic markers and efficient therapeutics. The fluorinated analog of deoxycytidine, gemcitabine and emerging FOLFIRINOX protocol (5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin) are the main chemotherapies to treat PDAC. The ErbB2/HER2 oncogenic receptor is commonly overexpressed in PDAC. In this context, we aimed to decipher the ErbB2-mediated mechanisms of chemoresistance to the two main chemotherapy protocols used to treat PDAC.ErbB2 knocking down (KD) in CAPAN-1 and CAPAN-2 cells led to an increased sensitivity to gemcitabine and an increased resistance to irinotecan/SN-38 both in vitro and in vivo (subcutaneous xenografts) This was correlated to an increase of hCNT1 and hCNT3 transporters and ABCG2, MRP1 and MRP2 ATP-binding cassette transporters expression and resistance to cell death. We also show that MRP2 is repressed following activation of JNK, Erk1/2 and NF-κB pathways by ErbB2. Finally, in datasets of human PDAC samples, ErbB2 and MRP2 expression was conversely correlated. Altogether, we propose that ErbB2 mediates several intracellular mechanisms linked to PDAC cell chemoresistance that may represent potential targets in order to ameliorate chemotherapy response and allow stratification of patients eligible for either gemcitabine or FOLFIRINOX treatment.
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- 2015
20. Flagellin-mediated protection against intestinal Yersinia pseudotuberculosis infection does not require interleukin-22.
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UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, Porte, Rémi, Van Maele, Laurye, Muñoz-Wolf, Natalia, Foligné, Benoit, Dumoutier, Laure, Tabareau, Julien, Cayet, Delphine, Gosset, Pierre, Jonckheere, Nicolas, Van Seuningen, Isabelle, Chabalgoity, A José, Simonet, Michel, Lamkanfi, Mohamed, Renauld, Jean-Christophe, Sirard, Jean-Claude, Carnoy, Christophe, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/MEXP - Médecine expérimentale, Porte, Rémi, Van Maele, Laurye, Muñoz-Wolf, Natalia, Foligné, Benoit, Dumoutier, Laure, Tabareau, Julien, Cayet, Delphine, Gosset, Pierre, Jonckheere, Nicolas, Van Seuningen, Isabelle, Chabalgoity, A José, Simonet, Michel, Lamkanfi, Mohamed, Renauld, Jean-Christophe, Sirard, Jean-Claude, and Carnoy, Christophe
- Abstract
Signaling through toll-like receptors (TLRs), the main receptors in innate immunity, is essential for the defense of mucosal surfaces. It was previously shown that systemic TLR5 stimulation by bacterial flagellin induces an immediate, transient interleukin-22 (IL-22)-dependent antimicrobial response to bacterial or viral infections of the mucosa. This process was dependent on the activation of type 3 innate lymphoid cells (ILCs). The objective of the present study was to analyze the effects of flagellin treatment in a murine model of oral infection with Yersinia pseudotuberculosis (an invasive, Gram-negative, enteropathogenic bacterium that targets the small intestine). We found that systemic administration of flagellin significantly increased the survival rate after intestinal infection (but not systemic infection) by Y. pseudotuberculosis This protection was associated with a low bacterial count in the gut and the spleen. In contrast, no protection was afforded by administration of the TLR4 agonist lipopolysaccharide - suggesting the presence of a flagellin-specific effect. Lastly, we found that TLR5- and MyD88-mediated signaling was required for the protective effects of flagellin, whereas neither lymphoid cells nor IL-22 were involved.
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- 2017
21. GATA-4/-6 and HNF-1/-4 families of transcription factors control the transcriptional regulation of the murine Muc5ac mucin during stomach development and in epithelial cancer cells.: Regulation of Muc5ac by GATA-6 and HNF-4α
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Jonckheere, Nicolas, Vincent, Audrey, Franquet-Ansart, Hélène, Witte-Bouma, Janneke, Korteland-van Male, Anita, Leteurtre, Emmanuelle, Renes, Ingrid, van Seuningen, Isabelle, Inserm UMR837 Team 5, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Laboratory of Pediatrics, Division of Neonatology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), This work was supported by a grant from l'Association François Aupetit (IVS). N. J is the recipient of a Ligue Nationale contre le Cancer (LNCC) postdoctoral fellowship. I V S is the recipient of a 'Contrat Hospitalier de Recherche Translationnelle'/CHRT 2010, AVIESAN., and Jonckheere, Nicolas
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MESH: Cell Differentiation ,MESH: Cell Line, Tumor ,MESH: GATA6 Transcription Factor ,MESH: Mice, Inbred BALB C ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,digestive system ,MESH: Stomach ,mucin ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,MESH: Promoter Regions, Genetic ,MESH: Gene Expression Regulation, Developmental ,MESH: Animals ,MESH: Neoplasms ,development ,MESH: Mice ,MESH: Organ Specificity ,GATA ,MESH: Mucin 5AC ,respiratory system ,HNF ,MESH: Epithelial Cells ,embryonic structures ,MESH: Transcriptional Activation ,MESH: Hepatocyte Nuclear Factor 4 ,transcription ,Muc5ac ,stomach - Abstract
International audience; During human embryonic and fetal development of the gastrointestinal tract, the gene encoding the MUC5AC mucin has a spatio-temporal pattern of expression restricted to the stomach. In order to better understand the molecular mechanisms responsible for this restricted pattern of expression, we have studied Muc5ac expression in the developing stomach of the mouse and correlated it to that of transcription factors known to be involved in cell differentiation programs during development. Our results indicate that GATA-6 and HNF-4α expression increased concomitantly with the induction of Muc5ac expression in embryonic stomach. We then studied Muc5ac transcriptional regulation by these transcription factors and showed that they all transactivate Muc5ac promoter. We also identified several active GATA-4/-5/-6 and HNF-1/-4 cis-elements using gel shift assays, chromatin immunoprecipitation and site-directed mutagenesis. Among all Muc5ac regulators, only GATA-6 and HNF-4a expression was concomitant to that of Muc5ac in the developing stomach. This is thus in favor of an important role for these two transcription factors as regulators of expression of the Muc5ac mucin during stomach development and in epithelial cancer cells.
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- 2012
22. Tif1γ Suppresses Murine Pancreatic Tumoral Transformation by a Smad4-Independent Pathway
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Vincent, David F., Gout, Johann, Chuvin, Nicolas, Arfi, Vanessa, Pommier, Roxane M., Bertolino, Philippe, Jonckheere, Nicolas, Ripoche, Doriane, Kaniewski, Bastien, Martel, Sylvie, Langlois, Jean-Baptiste, Goddard-Léon, Sophie, Colombe, Amélie, Janier, Marc, Van Seuningen, Isabelle, Losson, Régine, Valcourt, Ulrich, Treilleux, Isabelle, Dubus, Pierre, Bardeesy, Nabeel, and Bartholin, Laurent
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- 2012
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23. 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.
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Vasseur, Romain, Skrypek, Nicolas, Duchêne, Belinda, Renaud, Florence, Martínez-Maqueda, Daniel, Vincent, Audrey, Porchet, Nicole, Van Seuningen, Isabelle, and Jonckheere, Nicolas
- Abstract
Copyright of BBA - Gene Regulatory Mechanisms is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2015
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24. Evaluation of the expression of fatty acid synthase and O-GlcNAc transferase in patients with liver cancer by exploration of transcriptome databases and experimental approaches.
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Raab, Sadia, Very, Ninon, Duchêne, Belinda, Rybarczyk, Pierre, Jonckheere, Nicolas, El Yazidi-Belkoura, Ikram, and Lefebvre, Tony
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FATTY acid synthases ,LIVER cancer ,CANCER patients ,REVERSE transcriptase polymerase chain reaction ,RAPAMYCIN ,HEPATOCELLULAR carcinoma ,LIVER cells ,CALCINOSIS - Abstract
Tumor occurrence and development are closely related to metabolism abnormalities. One of the metabolic networks that is dysregulated during carcinogenesis is the fatty acid synthesis pathway, which is mainly controlled by fatty acid synthase (FASN). We previously demonstrated in proliferating HepG2 liver cancer cells that FASN expression depends on the catalytic activity of O-GlcNAc transferase (OGT) and the activation of the mechanistic/mammalian target of rapamycin (mTOR) pathway. The aim of the present study was to go further in these investigations by analyzing datasets and tissues of patients with liver cancer. To that purpose, transcriptome databases were explored, and reverse transcription-quantitative PCR, western blotting and immunohistochemistry were used. Database analyses revealed that FASN and OGT gene expression was higher in certain cancer tissues, including liver hepatocellular carcinoma, compared with that in non-cancerous tissues. At the protein level, FASN expression was higher in the liver cancer-derived cell lines HepG2 and Hep3B compared with the immortalized human hepatocytes IHH cell line. However, neither the expression of OGT nor of its product O-GlcNAcylation showed any significant difference among the three hepatic cell lines. Subsequently, the expression of FASN and OGT at the protein and mRNA levels was evaluated in human liver cancer and non-tumoral tissues from the same patients with different liver lesions. The results from western blotting demonstrated a significant increase in OGT ands O-GlcNAcylation expression in liver cancer tissues independently of the type of lesion characterizing the non-tumoral counterpart. As previously reported for HepG2 proliferating cells, the protein level of FASN was positively correlated with the activation of mTOR and, although a rather upward trend, a high variability in its expression was monitored between patients. However, the results from immunohistochemistry showed no particular modification for OGT and O-GlcNAcylation expression and a significant increase in FASN expression in cancer tissues compared with that in adjacent non-tumoral tissues. Non-significant changes were observed for FASN and OGT mRNA levels between tumoral and non-tumoral samples, with a high variability between patients. Taken together, these results demonstrated that FASN expression was higher in hepatic cancer tissues in comparison with non-tumoral tissues. Furthermore, OGT expression and activity were shown to vary greatly between cell or cancer type, making any generalization difficult. [ABSTRACT FROM AUTHOR]
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- 2022
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25. GATA-4/-6 and HNF-1/-4 families of transcription factors control the transcriptional regulation of the murine Muc5ac mucin during stomach development and in epithelial cancer cells.
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Jonckheere, Nicolas, Vincent, Audrey, Franquet-Ansart, Hélène, Witte-Bouma, Janneke, Korteland-van Male, Anita, Leteurtre, Emmanuelle, Renes, Ingrid B., and Van Seuningen, Isabelle
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REVERSE transcriptase ,POLYMERASE chain reaction ,HEPATOCYTE nuclear factors ,TRANSCRIPTION factors ,EPITHELIAL cell tumors ,GENE expression - Abstract
Abstract: During human embryonic and fetal development of the gastrointestinal tract, the gene encoding the MUC5AC mucin has a spatio–temporal pattern of expression restricted to the stomach. In order to better understand the molecular mechanisms responsible for this restricted pattern of expression, we have studied Muc5ac expression in the developing stomach of the mouse and correlated it to that of transcription factors known to be involved in cell differentiation programs during development. Our results indicate that GATA-6 and HNF-4α expression increased concomitantly with the induction of Muc5ac expression in embryonic stomach. We then studied Muc5ac transcriptional regulation by these transcription factors and showed that they all transactivate Muc5ac promoter. We also identified several active GATA-4/-5/-6 and HNF-1/-4 cis-elements using gel shift assays, chromatin immunoprecipitation and site-directed mutagenesis. Among all Muc5ac regulators, only GATA-6 and HNF-4a expression was concomitant to that of Muc5ac in the developing stomach. This is thus in favor of an important role for these two transcription factors as regulators of expression of the Muc5ac mucin during stomach development and in epithelial cancer cells. [Copyright &y& Elsevier]
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- 2012
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26. The Mucin MUC4 and Its Membrane Partner ErbB2 Regulate Biological Properties of Human CAPAN-2 Pancreatic Cancer Cells via Different Signalling Pathways.
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Jonckheere, Nicolas, Skrypek, Nicolas, Merlin, Johann, Dessein, Anne Frédérique, Dumont, Patrick, Leteurtre, Emmanuelle, Harris, Ann, Desseyn, Jean-Luc, Susini, Christiane, Frénois, Frédéric, and Van Seuningen, Isabelle
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MUCINS , *GENETIC regulation , *CANCER cells , *PANCREATIC cancer , *ONCOGENES - Abstract
The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells. [ABSTRACT FROM AUTHOR]
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- 2012
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27. Mucins and Pancreatic Cancer.
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Jonckheere, Nicolas, Skrypek, Nicolas, and Van Seuningen, Isabelle
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MUCINS , *PANCREATIC cancer , *BIOMARKERS , *GLYCOPROTEINS , *CANCER cells , *CARCINOGENESIS - Abstract
Pancreatic cancer is characterized by an often dramatic outcome (five year survival < 5%) related to a late diagnosis and a lack of efficient therapy. Therefore, clinicians desperately need new biomarkers and new therapeutic tools to develop new efficient therapies. Mucins belong to an ever increasing family of O-glycoproteins. Secreted mucins are the main component of mucus protecting the epithelia whereas membrane-bound mucins are thought to play important biological roles in cell-cell and cell-matrix interactions, in cell signaling and in modulating biological properties of cancer cells. In this review, we will focus on the altered expression pattern of mucins in pancreatic cancer, from the early neoplastic lesion Pancreatic Intraepithelial Neoplasia (PanIN) to invasive pancreatic carcinomas, and the molecular mechanisms (including genetic and epigenetic regulation) and signaling pathways known to control their expression. Moreover, we will discuss the recent advances about the biology of both secreted and membrane-bound mucins and their key roles in pancreatic carcinogenesis and resistance to therapy. Finally, we will discuss exciting opportunities that mucins offer as potential therapeutic targets in pancreatic cancer. [ABSTRACT FROM AUTHOR]
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- 2010
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28. Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma.
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Boukrout, Nihad, Souidi, Mouloud, Lahdaoui, Fatima, Duchêne, Belinda, Neve, Bernadette, Coppin, Lucie, Leteurtre, Emmanuelle, Torrisani, Jérôme, Van Seuningen, Isabelle, and Jonckheere, Nicolas
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PANCREATIC tumors ,ADENOCARCINOMA ,REVERSE transcriptase polymerase chain reaction ,IN vitro studies ,BIOLOGICAL models ,IN vivo studies ,XENOGRAFTS ,ANIMAL experimentation ,MICRORNA ,PRECIPITIN tests ,CELLULAR signal transduction ,CELL motility ,GENE expression ,TUMOR suppressor genes ,GLYCOPROTEINS ,DESCRIPTIVE statistics ,CELL proliferation ,DNA-binding proteins ,POLYMERASE chain reaction ,CELL lines ,MICE - Abstract
Simple Summary: We aimed at characterizing microRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. We investigated the MUC4-miR-210-3p reciprocal regulation and deciphered miR-210-3p biological roles in vitro and in vivo. We showed a MUC4-miR-210-3p negative feedback loop that involves NF-κB in PDAC-derived cells and the miR-210-3p anti-tumoral functions, suggesting a complex balance between antagonistic pro-oncogenic functions of the oncomucin MUC4 and anti-tumoral roles of the miR-210-3p. Background: Pancreatic adenocarcinoma (PDAC) is a deadly cancer with an extremely poor prognosis. MUC4 membrane-bound mucin is neoexpressed in early pancreatic neoplastic lesions and is associated with PDAC progression and chemoresistance. In cancers, microRNAs (miRNAs, small noncoding RNAs) are crucial regulators of carcinogenesis, chemotherapy response and even metastatic processes. In this study, we aimed at identifying and characterizing miRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. MiRnome analysis comparing MUC4-KD versus Mock cancer cells showed that MUC4 inhibition impaired miR-210-3p expression. Therefore, we aimed to better understand the miR-210-3p biological roles. Methods: miR-210-3p expression level was analyzed by RT-qPCR in PDAC-derived cell lines (PANC89 Mock and MUC4-KD, PANC-1 and MiaPACA-2), as well as in mice and patients tissues. The MUC4-miR-210-3p regulation was investigated using luciferase reporter construct and chromatin immunoprecipitation experiments. Stable cell lines expressing miR-210-3p or anti-miR-210-3p were established using CRISPR/Cas9 technology or lentiviral transduction. We evaluated the biological activity of miR-210-3p in vitro by measuring cell proliferation and migration and in vivo using a model of subcutaneous xenograft. Results: miR-210-3p expression is correlated with MUC4 expression in PDAC-derived cells and human samples, and in pancreatic PanIN lesions of Pdx1-Cre; LstopL-KrasG12D mice. MUC4 enhances miR-210-3p expression levels via alteration of the NF-κB signaling pathway. Chromatin immunoprecipitation experiments showed p50 NF-κB subunit binding on miR-210-3p promoter regions. We established a reciprocal regulation since miR-210-3p repressed MUC4 expression via its 3′-UTR. MiR-210-3p transient transfection of PANC89, PANC-1 and MiaPACA-2 cells led to a decrease in cell proliferation and migration. These biological effects were validated in cells overexpressing or knocked-down for miR-210-3p. Finally, we showed that miR-210-3p inhibits pancreatic tumor growth and proliferation in vivo. Conclusion: We identified a MUC4-miR-210-3p negative feedback loop in early-onset PDAC, but also revealed new functions of miR-210-3p in both in vitro and in vivo proliferation and migration of pancreatic cancer cells, suggesting a complex balance between MUC4 pro-oncogenic roles and miR-210-3p anti-tumoral effects. [ABSTRACT FROM AUTHOR]
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- 2021
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29. The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis.
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Stoup, Nicolas, Liberelle, Maxime, Schulz, Céline, Cavdarli, Sumeyye, Vasseur, Romain, Magnez, Romain, Lahdaoui, Fatima, Skrypek, Nicolas, Peretti, Fabien, Frénois, Frédéric, Thuru, Xavier, Melnyk, Patricia, Renault, Nicolas, Jonckheere, Nicolas, Lebègue, Nicolas, and Van Seuningen, Isabelle
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PANCREATIC tumors ,IN vitro studies ,IN vivo studies ,CELL migration ,EPIDERMAL growth factor ,ONCOGENES ,WESTERN immunoblotting ,MICROBIOLOGICAL assay ,ONE-way analysis of variance ,BIOINFORMATICS ,GLYCOPROTEINS ,CELL proliferation ,RESEARCH funding ,CELL lines - Abstract
Simple Summary: A feature of pancreatic cancer (PC) is the frequent overexpression of tyrosine kinase membrane receptor HER2 along with its membrane partner the MUC4 oncomucin in the early stages of the pancreatic carcinogenesis. However, therapeutic approaches targeting HER2 in PC are not efficient. MUC4 could indeed represent an alternative therapeutic strategy to target HER2 signaling pathway, but this approach needs to characterize MUC4/HER2 interaction at the molecular level. In this study, we successfully showed the impact of the EGF domains of MUC4 on HER2 binding affinity and demonstrated their "growth factor-like" biological activities in PC cells. Moreover, homology models of the MUC4
EGF /HER2 complexes allowed identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results allow a better understanding of the mechanisms involved in the MUC4/HER2 complex formation and may lead to the design of potential MUC4/HER2 inhibitors. The HER2 receptor and its MUC4 mucin partner form an oncogenic complex via an extracellular region of MUC4 encompassing three EGF domains that promotes tumor progression of pancreatic cancer (PC) cells. However, the molecular mechanism of interaction remains poorly understood. Herein, we decipher at the molecular level the role and impact of the MUC4EGF domains in the mediation of the binding affinities with HER2 and the PC cell tumorigenicity. We used an integrative approach combining in vitro bioinformatic, biophysical, biochemical, and biological approaches, as well as an in vivo study on a xenograft model of PC. In this study, we specified the binding mode of MUC4EGF domains with HER2 and demonstrate their "growth factor-like" biological activities in PC cells leading to stimulation of several signaling proteins (mTOR pathway, Akt, and β-catenin) contributing to PC progression. Molecular dynamics simulations of the MUC4EGF /HER2 complexes led to 3D homology models and identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results will pave the way to the design of potential MUC4/HER2 inhibitors targeting the EGF domains of MUC4. This strategy will represent a new efficient alternative to treat cancers associated with MUC4/HER2 overexpression and HER2-targeted therapy failure as a new adapted treatment to patients. [ABSTRACT FROM AUTHOR]- Published
- 2021
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30. The Human Mucin MUC4 Is Transcriptionally Regulated by Caudal-related Homeobox, Hepatocyte Nuclear Factors, Forkhead Box A, and GATA Endodermal Transcription Factors in Epithelial Cancer Cells.
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Jonckheere, Nicolas, Vincent, Audrey, Perrais, Michaël, Ducourouble, Marie-Paule, Korteland-van Male, Anita, Aubert, Jean-Pierre, Pigny, Pascal, Carraway, Kermit L., Freund, Jean-Noël, Renes, Ingrid B., and Van Seuningen, Isabelle
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MUCINS , *HOMEOBOX genes , *LIVER cells , *TRANSCRIPTION factors , *CANCER cells - Abstract
The human gene MUC4 encodes a large transmembrane mucin that is developmentally regulated and expressed along the undifferentiated pseudostratified epithelium, as early as 6.5 weeks during fetal development. Immunohistochemical analysis of Muc4 expression in developing mouse lung and gastrointestinal tract showed a different spatio-temporal pattern of expression before and after cytodifferentiation. The molecular mechanisms governing MUC4 expression during development are, however, unknown. Hepatocyte nuclear factors (HNF), forkhead box A (FOXA), GATA, and caudal-related homeobox transcription factors (TFs) are known to control cell differentiation of gut endoderm derived-tissues during embryonic development. They also control the expression of cell- and tissue-specific genes and may thus control MUC4 expression. To test this hypothesis, we studied and deciphered the molecular mechanisms responsible for MUC4 transcriptional regulation by these TFs. Experiments using small interfering RNA, cell co-transfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1α and -11β, FOXA1/A2, HNF-41α and -41γ, and GATA-4, -5, and -6 factors in a cell-specific manner. Binding of TFs was assessed by chromatin immunoprecipitation, and gel-shift assays. Altogether, these results demonstrate that MUC4 is a target gene of endodermal TFs and thus point out an important role for these TFs in regulating MUC4 expression during epithelial differentiation during development, cancer, and repair. [ABSTRACT FROM AUTHOR]
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- 2007
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31. A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-ß in pancreatic carcinogenesis.
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Jonckheere, Nicolas, Perrais, Michaël, Mariette, Christophe, Batra, Surinder K., Aubert, Jean-Pierre, Pigny, Pascal, and Van Seuningen, Isabelle
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MUCINS ,PANCREATIC cancer ,GENETIC transcription ,ACETYLATION ,CARCINOGENESIS - Abstract
MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-ß, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-ß in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-ß, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-ß induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-ß activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-ß is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-ß as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.Oncogene (2004) 23, 5729-5738. doi:10.1038/sj.onc.1207769 Published online 7 June 2004 [ABSTRACT FROM AUTHOR]
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- 2004
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32. Human MUC2 Mucin Gene Is Transcriptionally Regulated by Cdx Homeodomain Proteins in Gastrointestinal Carcinoma Cell Lines.
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Mesquita, Patrícia, Jonckheere, Nicolas, Almeida, Raquel, Ducourouble, Marie-Paule, Serpa, Jacinta, Silva, Elisabete, Pigny, Pascal, Silva, Filipe Santos, Reis, Celso, Silberg, Debra, Van Seuningen, Isabelle, and David, Leonor
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GASTROINTESTINAL diseases , *CANCER , *CELL lines , *METAPLASIA , *MUCINS , *TRANSCRIPTION factors - Abstract
In intestinal metaplasia and 30% of gastric carcinomas, MUC2 intestinal mucin and the intestine-specific transcription factors Cdx-1 and Cdx-2 are aberrantly expressed. The involvement of Cdx-1 and Cdx-2 in the intestinal development and their role in transcription of several intestinal genes support the hypothesis that Cdx-1 and/or Cdx-2 play important roles in the aberrant intestinal differentiation program of intestinal metaplasia and gastric carcinoma. To clarify the mechanisms of transcriptional regulation of the MUC2 mucin gene in gastric cells, pGL3 deletion constructs covering 2.6 kb of the human MUC2 promoter were used in transient transfection assays, enabling us to identify a relevant region for MUC2 transcription in all gastric cell lines. To evaluate the role of Cdx-1 and Cdx-2 in MUC2 transcription we performed co-transfection experiments with expression vectors encoding Cdx-1 and Cdx-2. In two of the four gastric carcinoma cell lines and in all colon carcinoma cell lines we observed transactivation of the MUC2 promoter by Cdx-2. Using gel shift assays we identified two Cdx-2 binding sites at -177/-171 and -191/-187. Only simultaneous mutation of the two sites resulted in inhibition of Cdx-2-mediated transactivation of MUC2 promoter, implying that both Cdx-2 sites are active. Finally, stable expression of Cdx-2 in a gastric cell line initially not expressing Cdx-2, led to induction of MUC2 expression. In conclusion, this work demonstrates that Cdx-2 activates the expression of MUC2 mucin gene in gastric cells, inducing an intestinal transdifferentiation phenotype that parallels what is observed both in intestinal metaplasia and some gastric carcinomas. [ABSTRACT FROM AUTHOR]
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- 2003
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33. Mg 2+ Transporters in Digestive Cancers.
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Auwercx, Julie, Rybarczyk, Pierre, Kischel, Philippe, Dhennin-Duthille, Isabelle, Chatelain, Denis, Sevestre, Henri, Van Seuningen, Isabelle, Ouadid-Ahidouch, Halima, Jonckheere, Nicolas, and Gautier, Mathieu
- Abstract
Despite magnesium (Mg
2+ ) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg2+ homeostasis is regulated by Mg2+ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg2+ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg2+ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg2+ transporters' expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg2+ transporters in the regulation of cancer cell fates and oncogenic signaling pathways. [ABSTRACT FROM AUTHOR]- Published
- 2021
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34. Unsupervised Hierarchical Clustering of Pancreatic Adenocarcinoma Dataset from TCGA Defines a Mucin Expression Profile that Impacts Overall Survival.
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Jonckheere, Nicolas, Auwercx, Julie, Hadj Bachir, Elsa, Coppin, Lucie, Boukrout, Nihad, Vincent, Audrey, Neve, Bernadette, Gautier, Mathieu, Treviño, Victor, and Van Seuningen, Isabelle
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GLYCOPROTEIN analysis , *ADENOCARCINOMA , *CLUSTER analysis (Statistics) , *COMPARATIVE studies , *GENE mapping , *GLYCOPROTEINS , *MESSENGER RNA , *PANCREATIC tumors , *SURVIVAL analysis (Biometry) , *TUMOR markers , *GENE expression profiling , *DESCRIPTIVE statistics - Abstract
Simple Summary: Pancreatic cancer has a dramatic outcome (survival curve < 6 months) that is the consequence of late diagnosis and the lack of efficient therapy. We investigated the relationship between the 22 mucin gene expression and the patient survival in pancreatic cancer datasets that provide a comprehensive mapping of transcriptomic alterations occurring during carcinogenesis. Using unsupervised hierarchical clustering analysis of mucin gene expression patterns, we identified two major clusters of patients: atypical mucin signature (#1; MUC15, MUC14/EMCN, and MUC18/MCAM) and membrane-bound mucin signature (#2; MUC1, -4, -16, -17, -20, and -21). The signature #2 is associated with shorter overall survival, suggesting that the pattern of membrane-bound mucin expression could be a new prognostic marker for PDAC patients. Mucins are commonly associated with pancreatic ductal adenocarcinoma (PDAC) that is a deadly disease because of the lack of early diagnosis and efficient therapies. There are 22 mucin genes encoding large O-glycoproteins divided into two major subgroups: membrane-bound and secreted mucins. We investigated mucin expression and their impact on patient survival in the PDAC dataset from The Cancer Genome Atlas (PAAD-TCGA). We observed a statistically significant increased messenger RNA (mRNA) relative level of most of the membrane-bound mucins (MUC1/3A/4/12/13/16/17/20), secreted mucins (MUC5AC/5B), and atypical mucins (MUC14/18) compared to normal pancreas. We show that MUC1/4/5B/14/17/20/21 mRNA levels are associated with poorer survival in the high-expression group compared to the low-expression group. Using unsupervised clustering analysis of mucin gene expression patterns, we identified two major clusters of patients. Cluster #1 harbors a higher expression of MUC15 and atypical MUC14/MUC18, whereas cluster #2 is characterized by a global overexpression of membrane-bound mucins (MUC1/4/16/17/20/21). Cluster #2 is associated with shorter overall survival. The patient stratification appears to be independent of usual clinical features (tumor stage, differentiation grade, lymph node invasion) suggesting that the pattern of membrane-bound mucin expression could be a new prognostic marker for PDAC patients. [ABSTRACT FROM AUTHOR]
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- 2020
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35. TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727.
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Drubay, Vincent, Skrypek, Nicolas, Cordiez, Lucie, Vasseur, Romain, Schulz, Céline, Boukrout, Nihad, Duchêne, Belinda, Coppin, Lucie, Van Seuningen, Isabelle, and Jonckheere, Nicolas
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ADENOCARCINOMA ,ANTIMETABOLITES ,BIOMARKERS ,CELLULAR signal transduction ,DRUG resistance ,GENETIC mutation ,PANCREATIC tumors ,TRANSFORMING growth factors-beta ,TREATMENT effectiveness ,NEURAL pathways ,PHARMACODYNAMICS - Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer. [ABSTRACT FROM AUTHOR]
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- 2018
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36. Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosisInfection Does Not Require Interleukin-22
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Porte, Rémi, Van Maele, Laurye, Muñoz-Wolf, Natalia, Foligné, Benoit, Dumoutier, Laure, Tabareau, Julien, Cayet, Delphine, Gosset, Pierre, Jonckheere, Nicolas, Van Seuningen, Isabelle, Chabalgoity, José A., Simonet, Michel, Lamkanfi, Mohamed, Renauld, Jean-Christophe, Sirard, Jean-Claude, and Carnoy, Christophe
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ABSTRACTSignaling through Toll-like receptors (TLRs), the main receptors in innate immunity, is essential for the defense of mucosal surfaces. It was previously shown that systemic TLR5 stimulation by bacterial flagellin induces an immediate, transient interleukin-22 (IL-22)-dependent antimicrobial response to bacterial or viral infections of the mucosa. This process was dependent on the activation of type 3 innate lymphoid cells (ILCs). The objective of the present study was to analyze the effects of flagellin treatment in a murine model of oral infection with Yersinia pseudotuberculosis(an invasive, Gram-negative, enteropathogenic bacterium that targets the small intestine). We found that systemic administration of flagellin significantly increased the survival rate after intestinal infection (but not systemic infection) by Y. pseudotuberculosis. This protection was associated with a low bacterial count in the gut and the spleen. In contrast, no protection was afforded by administration of the TLR4 agonist lipopolysaccharide, suggesting the presence of a flagellin-specific effect. Lastly, we found that TLR5- and MyD88-mediated signaling was required for the protective effects of flagellin, whereas neither lymphoid cells nor IL-22 was involved.
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- 2016
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37. Bile acids regulate MUC4 mucin gene expression at the transcriptional level in esophagus cancer cells. PI3K appears as the major signaling pathway
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Mariette, Christophe, Perrais, Michael, Pigny, Pascal, Jonckheere, Nicolas, Leteurtre, Emmanuelle, Aubert, Jean-Pierre, Triboulet, Jean-Pierre, and Van Seuningen, Isabelle
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- 2003
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38. T1998 The Muc4 Membrane-Bound Mucin Alters In Vitro and In Vivo Biological Properties of Human Pancreatic Cancer Cells.
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Jonckheere, Nicolas, Skrypek, Nicolas, Saint-Laurent, Nathalie, Susini, Christiane, and VAN SEUNINGEN, Isabelle
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- 2009
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39. Transcriptional regulation of human mucin gene MUC4 by TGF-β and EGF/TGF-α in pancreatic cancer cells involves a complex cross-talk between the Smads, MAPK, P13K, and PKA signaling pathways
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Jonckheere, Nicolas, Perrais, Michael, Mariette, Christophe, Ducourouble, Marie-Paule, Aubert, Jean-Pierre, Pigny, Pascal, and Van Seuningen, Isabelle
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- 2003
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40. Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma
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Nihad Boukrout, Mouloud Souidi, Fatima Lahdaoui, Belinda Duchêne, Bernadette Neve, Lucie Coppin, Emmanuelle Leteurtre, Jérôme Torrisani, Isabelle Van Seuningen, Nicolas Jonckheere, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Jonckheere, Nicolas, and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Cancer Research ,anti-tumoral miR ,pancreatic cancer ,MUC4 ,miR-210-3p ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,sense organs ,Article ,RC254-282 - Abstract
Simple Summary We aimed at characterizing microRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. We investigated the MUC4-miR-210-3p reciprocal regulation and deciphered miR-210-3p biological roles in vitro and in vivo. We showed a MUC4-miR-210-3p negative feedback loop that involves NF-κB in PDAC-derived cells and the miR-210-3p anti-tumoral functions, suggesting a complex balance between antagonistic pro-oncogenic functions of the oncomucin MUC4 and anti-tumoral roles of the miR-210-3p. Abstract Background: Pancreatic adenocarcinoma (PDAC) is a deadly cancer with an extremely poor prognosis. MUC4 membrane-bound mucin is neoexpressed in early pancreatic neoplastic lesions and is associated with PDAC progression and chemoresistance. In cancers, microRNAs (miRNAs, small noncoding RNAs) are crucial regulators of carcinogenesis, chemotherapy response and even metastatic processes. In this study, we aimed at identifying and characterizing miRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. MiRnome analysis comparing MUC4-KD versus Mock cancer cells showed that MUC4 inhibition impaired miR-210-3p expression. Therefore, we aimed to better understand the miR-210-3p biological roles. Methods: miR-210-3p expression level was analyzed by RT-qPCR in PDAC-derived cell lines (PANC89 Mock and MUC4-KD, PANC-1 and MiaPACA-2), as well as in mice and patients tissues. The MUC4-miR-210-3p regulation was investigated using luciferase reporter construct and chromatin immunoprecipitation experiments. Stable cell lines expressing miR-210-3p or anti-miR-210-3p were established using CRISPR/Cas9 technology or lentiviral transduction. We evaluated the biological activity of miR-210-3p in vitro by measuring cell proliferation and migration and in vivo using a model of subcutaneous xenograft. Results: miR-210-3p expression is correlated with MUC4 expression in PDAC-derived cells and human samples, and in pancreatic PanIN lesions of Pdx1-Cre; LstopL-KrasG12D mice. MUC4 enhances miR-210-3p expression levels via alteration of the NF-κB signaling pathway. Chromatin immunoprecipitation experiments showed p50 NF-κB subunit binding on miR-210-3p promoter regions. We established a reciprocal regulation since miR-210-3p repressed MUC4 expression via its 3′-UTR. MiR-210-3p transient transfection of PANC89, PANC-1 and MiaPACA-2 cells led to a decrease in cell proliferation and migration. These biological effects were validated in cells overexpressing or knocked-down for miR-210-3p. Finally, we showed that miR-210-3p inhibits pancreatic tumor growth and proliferation in vivo. Conclusion: We identified a MUC4-miR-210-3p negative feedback loop in early-onset PDAC, but also revealed new functions of miR-210-3p in both in vitro and in vivo proliferation and migration of pancreatic cancer cells, suggesting a complex balance between MUC4 pro-oncogenic roles and miR-210-3p anti-tumoral effects.
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- 2021
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41. Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells.
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Tréhoux, Solange, Lahdaoui, Fatima, Delpu, Yannick, Renaud, Florence, Leteurtre, Emmanuelle, Torrisani, Jérôme, Jonckheere, Nicolas, and Van Seuningen, Isabelle
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PANCREATIC cancer , *MICRORNA , *ONCOGENES , *MUCOPROTEINS ,MUCIN analysis - Abstract
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 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. [ABSTRACT FROM AUTHOR]
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- 2015
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42. The MUC1 mucin regulates the tumorigenic properties of human esophageal adenocarcinomatous cells.
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Gronnier, Caroline, Bruyère, Emilie, Lahdaoui, Fatima, Jonckheere, Nicolas, Perrais, Michaël, Leteurtre, Emmanuelle, Piessen, Guillaume, Mariette, Christophe, and Van Seuningen, Isabelle
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ONCOGENIC viruses , *ESOPHAGEAL cancer , *ADENOCARCINOMA , *CELL proliferation , *GENE expression , *XENOGRAFTS , *CELL lines - Abstract
MUC1 is a membrane-bound mucin known to participate in tumor proliferation. It has been shown that MUC1 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplasia to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is gastro-esophageal reflux and MUC1 was previously shown to be up-regulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC1 plays a role in biological properties of human esophageal cancer cells. For that, a stable MUC1-deficient esophageal cancer cell line was established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of MUC1-deficient cells were analyzed. Our results show that esophageal cancer cells lacking MUC1 were less proliferative and had decreased migration and invasion properties. These alterations were accompanied by a decreased activity of NFKB p65, Akt and MAPK (p44/42, JNK and p38) pathways. MCM6 and TSG101 tumor-associated markers were also decreased. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC1. Altogether, the data indicate that MUC1 plays a key role in proliferative, migrating and invasive properties of esophageal cancer cells as well as in tumor growth promotion. MUC1 mucin appears thus as a good therapeutic target to slow down esophageal tumor progression. [ABSTRACT FROM AUTHOR]
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- 2014
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43. Mg2+ Transporters in Digestive Cancers
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Halima Ouadid-Ahidouch, Julie Auwercx, Henri Sevestre, Nicolas Jonckheere, Pierre Rybarczyk, Denis Chatelain, Philippe Kischel, Isabelle Dhennin-Duthille, Mathieu Gautier, Isabelle Van Seuningen, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Jonckheere, Nicolas, Laboratoire de Physiologie Cellulaire et Moléculaire - UR UPJV 4667 (LPCM), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, and This research was funded by the 'Ministère de l’Enseignement Supérieur de la Recherche et de l’Innovation' (J.A.), the 'Université de Picardie Jules Verne (UPJV)' (J.A., P.K., I.D.D., H.O.A., and M.G.), the 'Université de Lille' (I.V.S. and N.J.), 'le CHU Amiens-Picardie' (P.R., D.C., and H.S.), the 'Institut National de la Santé et de la Recherche Médicale (Inserm) ' (I.V.S. and NJ), the 'Centre National de la Recherche Scientifique (CNRS)' (I.V.S. and N.J.), 'La Ligue Nationale contre le Cancer' (comité Septentrion N.J. and M.G.), and 'l’Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail' (N.J. and M.G.).
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0301 basic medicine ,Cell physiology ,[SDV]Life Sciences [q-bio] ,overall survival ,Cell ,CBS domain ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,lcsh:TX341-641 ,Review ,Biology ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,TRPM6 ,medicine ,Animals ,Homeostasis ,Humans ,Magnesium ,Cation Transport Proteins ,Gastrointestinal Neoplasms ,Ion Transport ,Nutrition and Dietetics ,digestive cancers ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Transporter ,TCGA ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,3. Good health ,Cell biology ,Solute carrier family ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Disease Susceptibility ,lcsh:Nutrition. Foods and food supply ,Biomarkers ,Cation transport ,magnesium transporters ,Protein Binding ,Signal Transduction ,Food Science - Abstract
Despite magnesium (Mg2+) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg2+ homeostasis is regulated by Mg2+ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg2+ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg2+ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg2+ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg2+ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.
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- 2021
44. Fine-tuning autophagy in pancreatic adenocarcinoma: full blockage is required
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Nicolas Jonckheere, Isabelle Van Seuningen, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Jonckheere, Nicolas
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Pancreatic ductal adenocarcinoma ,[SDV]Life Sciences [q-bio] ,ATG5 ,Autophagy ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,General Medicine ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,medicine.disease_cause ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cytoplasm ,030220 oncology & carcinogenesis ,Pancreatic cancer ,medicine ,Cancer research ,Adenocarcinoma ,Carcinogenesis ,Homeostasis ,ComputingMilieux_MISCELLANEOUS - Abstract
Autophagy is a physiological process of cellular component recycling promoting cell survival and homeostasis under unfavorable conditions. Pancreatic ductal adenocarcinoma (PDAC) (90–95% of pancreatic cancer) has been associated with multiple metabolic alterations including autophagy. Because of its supporting role in tumor growth, inhibition of autophagy has been proposed as a treatment of pancreatic cancer (1,2). Autophagy process is regulated by autophagy-related proteins (ATGs) necessary for the autophagosome formation and subsequent delivering of cytoplasmic content for degradation by lysosomes. Among these proteins, Atg5 is a key player for autophagy onset but little is known about its role in tumorigenesis (3).
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- 2019
45. Colon cancer stemness as a reversible epigenetic state: Implications for anticancer therapies
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Aïcha Ouelkdite-Oumouchal, Julie Leclerc, Audrey Vincent, Bernadette Neve, Isabelle Van Seuningen, Mouloud Souidi, Jonckheere, Nicolas, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 'Institut National de la Santé et de la Recherche Médicale', (Inserm), 'Centre National de la Recherche Scientifique' (CNRS), 'la Ligue Nationale contre le Cancer' (Committees 59, 60 and 62)., Laboratoire d'Études Rurales (LER), Université Lumière - Lyon 2 (UL2), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire Epigenetique et Cancer, Centre National de la Recherche Scientifique (CNRS), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Laboratoire Epigénétique et Cancer (LEC), Département Biologie des Génomes (DBG), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Histology ,Colorectal cancer ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Review ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cancer stem cell ,Genetics ,medicine ,Chromatin modifying enzymes ,Epigenetics ,CD133 ,CD44 ,Molecular Biology ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,biology ,Cluster of differentiation ,Cancer stem cells ,Cancer ,Cell Biology ,medicine.disease ,3. Good health ,Colon cancer ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Histone deacetylase ,CD166 - Abstract
International audience; The recent discovery of cancer cell plasticity, i.e. their ability to reprogram into cancer stem cells (CSCs) either naturally or under chemotherapy and/or radiotherapy, has changed, once again, the way we consider cancer treatment. If cancer stemness is a reversible epigenetic state rather than a genetic identity, opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs. However, the systematic use of DNA methyltransferase and histone deacetylase inhibitors, alone or in combination, in advanced solid tumors including colorectal cancers, regardless of their molecular subtypes, does not seem to be the best strategy. In this review, we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells. We raise questions about the relevant use of currently available epigenetic inhibitors (epidrugs) while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms. These markers include the three cluster of differentiation CD133, CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and . Finally, we describe current treatment strategies using epidrugs, and we hypothesize that, using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression, we could identify better candidates for epienzyme targeting.
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- 2019
46. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting
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Nicolas Jonckheere, Isabelle Van Seuningen, Romain Vasseur, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Jonckheere, Nicolas, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
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0301 basic medicine ,Cell signaling ,pancreatic cancer ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,medicine.disease_cause ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,cell signaling ,PI3K/AKT/mTOR pathway ,Genetics ,Mutation ,Tumor microenvironment ,therapy ,Oncogene ,metabolism reprogramming ,Hematology ,medicine.disease ,3. Good health ,Pancreatic Neoplasms ,Genes, ras ,030104 developmental biology ,Oncology ,Cancer research ,Adenocarcinoma ,Signal transduction ,K-RAS ,Carcinoma, Pancreatic Ductal ,Signal Transduction - Abstract
International audience; RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90 %). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral...). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.
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- 2017
47. Mucins and tumor resistance to chemotherapeutic drugs
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Nicolas Jonckheere, Isabelle Van Seuningen, Nicolas Skrypek, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Jonckheere, Nicolas
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Cancer Research ,Epithelial-Mesenchymal Transition ,medicine.medical_treatment ,Cell ,Antineoplastic Agents ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,medicine.disease_cause ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Neoplasms ,Genetics ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Chemotherapy ,Polymorphism, Genetic ,Mucin ,Mucins ,Cancer ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Cancer cell ,Immunology ,Inactivation, Metabolic ,Cancer research ,Carcinogenesis ,Drug metabolism - Abstract
International audience; Epithelial cancer patients not considered eligible for surgical resection frequently benefit from chemotherapy. Chemotherapy is the treatment of cancer with one or combination of cytotoxic or cytostatic drugs. Recent advances in chemotherapy allowed a great number of cancer patients to receive treatment with significant results. Unfortunately, resistance to chemotherapeutic drug treatment is a major challenge for clinicians in the majority of epithelial cancers because it is responsible for the inefficiency of therapies. Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Implications of mucins have been described in relation to cancer cell behavior and cell signaling pathways associated with epithelial tumorigenesis. Because of the frequent alteration of the pattern of mucin expression in cancers as well as their structural and functional characteristics, mucins are thought to also be involved in response to therapies. In this report, we review the roles of mucins in chemoresistance and the associated underlying molecular mechanisms (physical barrier, resistance to apoptosis, drug metabolism, cell stemness, epithelial-mesenchymal transition) and discuss the therapeutic tools/strategies and/or prognosis biomarkers for personalized chemotherapy that could be proposed from these studies.
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- 2014
48. Comment on: Functional MUC4 suppress epithelial-mesenchymal transition in lung adenocarcinoma metastasis. Gao L, Liu J, Zhang B, Zhang H, Wang D, Zhang T, Liu Y, Wang C. Tumour Biol. 2013, in press
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Nicolas Jonckheere, Isabelle Van Seuningen, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Lille Nord (France), Jonckheere, Nicolas, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
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Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,epithelial mesenchymal transition ,Zhàng ,oncomucin ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Adenocarcinoma ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,Lung cancer ,030304 developmental biology ,0303 health sciences ,Lung ,Mucin-4 ,business.industry ,Mucin ,General Medicine ,medicine.disease ,lung adenocarcinoma ,Nuclear translocation ,3. Good health ,medicine.anatomical_structure ,MUC4 ,030220 oncology & carcinogenesis ,Cancer research ,sense organs ,business - Abstract
Comment onFunctional MUC4 Suppress Epithelial-Mesenchymal Transition in Lung Adenocarcinoma MetastasisL Gao et al. Tumour Biol 35 (2), 1335-41. Feb 2014. PMID 24037917.The mucin MUC4 is a high molecular weight membrane-bound transmembrane glycoprotein that is frequently detected in invasive and metastatic cancer. The overexpression of M …; International audience; Gao and collaborators (Tumour Biol, 2013) have investigated the role of mucin 4 (MUC4) in lung cancer and have concluded that a loss of MUC4 results in epithelial mesenchymal transition via beta-catenin nuclear translocation and that MUC4 expression is correlated with a risk of lymph node metastasis in a cohort of 20 lung adenocarcinoma patients. This surprising analysis is contradictory to most of the scientific knowledge and literature regarding MUC4 contribution in epithelial cancers that is very hardly discussed in their manuscript.
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- 2014
49. Membrane-bound mucin modular domains: from structure to function
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Nicolas Skrypek, Isabelle Van Seuningen, Nicolas Jonckheere, Frédéric Frénois, Inserm UMR837 Team 5, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, NJ postdoctoral fellowship Ligue Nationale Contre le Cancer (LNCC), NS PhD fellowship Centre Hospitalier Régional et Universitaire (CHRU) de Lille/région Nord-Pas de Calais. FF postdoctoral fellowship Fondation pour la Recherche Médicale (FRM). Ligue Nationale Contre le Cancer (Equipe Labellisée Ligue 2010, IVS). IVS Contrat Hospitalier de Recherche Translationnelle'/CHRT 2010, AVIESAN., Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Jonckheere, Nicolas
- Subjects
Membrane bound ,Functional features ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Computational biology ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Structural organization ,business.industry ,Mucin ,Structure function ,Mucins ,General Medicine ,Modular design ,Biological Evolution ,Protein Structure, Tertiary ,030220 oncology & carcinogenesis ,business ,Function (biology) - Abstract
International audience; Mucins belong to a heterogeneous family of large O-glycoproteins composed of a long peptidic chain called apomucin on which are linked hundreds of oligosaccharidic chains. Among mucins, membrane-bound mucins are modular proteins and have a structural organization usually containing Pro/Thr/Ser-rich O-glycosylated domains (PTS), EGF-like and SEA domains. Via these modular domains, the membrane-bound mucins participate in cell signalling and cell interaction with their environment in normal and pathological conditions. Moreover, the recent knowledge of these domains and their biological activities led to the development of new therapeutic approaches involving mucins. In this review, we show 3D structures of EGF and SEA domains. We also describe the functional features of the evolutionary conserved domains of membrane-bound mucins and discuss consequences of splice events.
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- 2013
50. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family
- Author
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Nicolas Skrypek, Belinda Duchêne, I. Van Seuningen, Nicolas Jonckheere, M Hebbar, Emmanuelle Leteurtre, Jonckheere, Nicolas, Inserm UMR837 Team 5, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, NJ postdoctoral fellowship Ligue Nationale Contre le Cancer (LNCC), NS PhD fellowship Centre Hospitalier Régional et Universitaire (CHRU) de Lille/région Nord-Pas de Calais. Ligue Nationale Contre le Cancer (Equipe Labellisée Ligue 2010, IVS). IVS Contrat Hospitalier de Recherche Translationnelle'/CHRT 2010, AVIESAN., Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service d'oncologie médicale, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Centre de Biologie-Pathologie
- Subjects
Male ,hCNT1 ,Cancer Research ,pancreatic cancer ,Equilibrative nucleoside transporter 1 ,Deoxycytidine ,NF-κB ,Small hairpin RNA ,Concentrative nucleoside transporter ,0302 clinical medicine ,Pancreatic tumor ,0303 health sciences ,biology ,gemcitabine ,Deoxycytidine kinase ,Middle Aged ,3. Good health ,Gene Expression Regulation, Neoplastic ,Biochemistry ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Multigene Family ,Female ,medicine.drug ,Antimetabolites, Antineoplastic ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Adenocarcinoma ,Models, Biological ,Article ,Equilibrative Nucleoside Transporter 1 ,03 medical and health sciences ,mucin ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Pancreatic cancer ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Aged ,Mucin-4 ,Membrane Transport Proteins ,medicine.disease ,Gemcitabine ,Pancreatic Neoplasms ,Cell culture ,Drug Resistance, Neoplasm ,MUC4 ,biology.protein ,Cancer research ,sense organs - Abstract
International audience; The fluorinated analog of deoxycytidine, Gemcitabine (Gemzar), is the main chemotherapeutic drug in pancreatic cancer, but survival remains weak mainly because of the high resistance of tumors to the drug. Recent works have shown that the mucin MUC4 may confer an advantage to pancreatic tumor cells by modifying their susceptibility to drugs. However, the cellular mechanism(s) responsible for this MUC4-mediated resistance is unknown. The aim of this work was to identify the cellular mechanisms responsible for gemcitabine resistance linked to MUC4 expression. CAPAN-2 and CAPAN-1 adenocarcinomatous pancreatic cancer (PC) cell lines were used to establish stable MUC4-deficient clones (MUC4-KD) by shRNA interference. Measurement of the IC50 index using tetrazolium salt test indicated that MUC4-deficient cells were more sensitive to gemcitabine. This was correlated with increased Bax/BclXL ratio and apoptotic cell number. Expression of Equilibrative/Concentrative Nucleoside Transporter (hENT1, hCNT1/3), deoxycytidine kinase (dCK), ribonucleotide reductase (RRM1/2) and Multidrug-Resistance Protein (MRP3/4/5) was evaluated by quantitative RT-PCR (qRT-PCR) and western blotting. Alteration of MRP3, MRP4, hCNT1 and hCNT3 expression was observed in MUC4-KD cells, but only hCNT1 alteration was correlated to MUC4 expression and sensitivity to gemcitabine. Decreased activation of MAPK, JNK and NF-κB pathways was observed in MUC4-deficient cells, in which the NF-κB pathway was found to have an important role in both sensitivity to gemcitabine and hCNT1 regulation. Finally, and in accordance with our in vitro data, we found that MUC4 expression was conversely correlated to that of hCNT1 in tissues from patients with pancreatic adenocarcinoma. This work describes a new mechanism of PC cell resistance to gemcitabine, in which the MUC4 mucin negatively regulates the hCNT1 transporter expression via the NF-κB pathway. Altogether, these data point out to MUC4 and hCNT1 as potential targets to ameliorate the response of pancreatic tumors to gemcitabine treatment.
- Published
- 2013
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