259 results on '"Seuningen, Isabelle"'
Search Results
2. ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells
- Author
-
Cicero, Julien, Trouvilliez, Sarah, Palma, Martine, Ternier, Gaetan, Decoster, Laurine, Happernegg, Eloise, Barois, Nicolas, Van Outryve, Alexandre, Dehouck, Lucie, Bourette, Roland P., Adriaenssens, Eric, Lagadec, Chann, Tarhan, Cagatay Mehmet, Collard, Dominique, Souguir, Zied, Vandenhaute, Elodie, Maubon, Grégory, Sipieter, François, Borghi, Nicolas, Shimizu, Fumitaka, Kanda, Takashi, Giacobini, Paolo, Gosselet, Fabien, Maubon, Nathalie, Le Bourhis, Xuefen, Van Seuningen, Isabelle, Mysiorek, Caroline, and Toillon, Robert-Alain
- Published
- 2023
- Full Text
- View/download PDF
3. Single-Cell Analysis May Shed New Lights on the Role of LncRNAs in Chemoresistance in Gastrointestinal Cancers
- Author
-
Neve, Bernadette, Jonckheere, Nicolas, Vincent, Audrey, Van Seuningen, Isabelle, Barciszewski, Jan, Series Editor, Erdmann, Volker A., Founding Editor, Rajewsky, Nikolaus, Series Editor, and Jurga, Stefan, editor
- Published
- 2020
- Full Text
- View/download PDF
4. Mucin expression, epigenetic regulation and patient survival: A toolkit of prognostic biomarkers in epithelial cancers
- Author
-
Jonckheere, Nicolas, Vincent, Audrey, Neve, Bernadette, and Van Seuningen, Isabelle
- Published
- 2021
- Full Text
- View/download PDF
5. Long non-coding RNAs: the tentacles of chromatin remodeler complexes
- Author
-
Neve, Bernadette, Jonckheere, Nicolas, Vincent, Audrey, and Van Seuningen, Isabelle
- Published
- 2021
- Full Text
- View/download PDF
6. Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer
- Author
-
Roberti, Maria Paula, Yonekura, Satoru, Duong, Connie P. M., Picard, Marion, Ferrere, Gladys, Tidjani Alou, Maryam, Rauber, Conrad, Iebba, Valerio, Lehmann, Christian H. K., Amon, Lukas, Dudziak, Diana, Derosa, Lisa, Routy, Bertrand, Flament, Caroline, Richard, Corentin, Daillère, Romain, Fluckiger, Aurélie, Van Seuningen, Isabelle, Chamaillard, Mathias, Vincent, Audrey, Kourula, Stephanie, Opolon, Paule, Ly, Pierre, Pizzato, Eugénie, Becharef, Sonia, Paillet, Juliette, Klein, Christophe, Marliot, Florence, Pietrantonio, Filippo, Benoist, Stéphane, Scoazec, Jean-Yves, Dartigues, Peggy, Hollebecque, Antoine, Malka, David, Pagès, Franck, Galon, Jérôme, Gomperts Boneca, Ivo, Lepage, Patricia, Ryffel, Bernard, Raoult, Didier, Eggermont, Alexander, Vanden Berghe, Tom, Ghiringhelli, François, Vandenabeele, Peter, Kroemer, Guido, and Zitvogel, Laurence
- Published
- 2020
- Full Text
- View/download PDF
7. MUC1 Mitigates Renal Injury and Inflammation in Endotoxin Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-Inflammatory Macrophages Infiltration
- Author
-
Gibier, Jean-Baptiste, Swierczewski, Thomas, Csanyi, Marie, Hemon, Brigitte, Glowacki, Francois, Maboudou, Patrice, Van Seuningen, Isabelle, Cauffiez, Christelle, Pottier, Nicolas, Aubert, Sebastien, Perrais, Michael, and Gnemmi, Viviane
- Published
- 2021
- Full Text
- View/download PDF
8. Directions to overcome therapy resistance in cancer
- Author
-
Nussinov, Ruth, Weichhart, Thomas, Dlamini, Zodwa, Gibbons, Don L., Van Seuningen, Isabelle, Konen, Jessica, and Ju, Huai-Qiang
- Published
- 2024
- Full Text
- View/download PDF
9. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting
- Author
-
Jonckheere, Nicolas, Vasseur, Romain, and Van Seuningen, Isabelle
- Published
- 2017
- Full Text
- View/download PDF
10. Galectin-3 modulates epithelial cell adaptation to stress at the ER-mitochondria interface
- Author
-
Coppin, Lucie, Jannin, Arnaud, Ait Yahya, Emilie, Thuillier, Caroline, Villenet, Céline, Tardivel, Meryem, Bongiovanni, Antonino, Gaston, Cécile, de Beco, Simon, Barois, Nicolas, van Seuningen, Isabelle, Durand, Emmanuelle, Bonnefond, Amélie, Vienne, Jean-Claude, Vamecq, Joseph, Figeac, Martin, Vincent, Audrey, Delacour, Delphine, Porchet, Nicole, and Pigny, Pascal
- Published
- 2020
- Full Text
- View/download PDF
11. Publisher Correction: MUC4-ErbB2 Oncogenic Complex: Binding studies using Microscale Thermophoresis
- Author
-
Liberelle, Maxime, Magnez, Romain, Thuru, Xavier, Bencheikh, Yamina, Ravez, Severine, Quenon, Camille, Drucbert, Anne-Sophie, Foulon, Catherine, Melnyk, Patricia, Van Seuningen, Isabelle, and Lebègue, Nicolas
- Published
- 2020
- Full Text
- View/download PDF
12. MUC4-ErbB2 Oncogenic Complex: Binding studies using Microscale Thermophoresis
- Author
-
Liberelle, Maxime, Magnez, Romain, Thuru, Xavier, Bencheikh, Yamina, Ravez, Severine, Quenon, Camille, Drucbert, Anne-Sophie, Foulon, Catherine, Melnyk, Patricia, Van Seuningen, Isabelle, and Lebègue, Nicolas
- Published
- 2019
- Full Text
- View/download PDF
13. MUC1 Drives the Progression and Chemoresistance of Clear Cell Renal Carcinomas.
- Author
-
Bourdon, Emma, Swierczewski, Thomas, Goujon, Marine, Boukrout, Nihad, Fellah, Sandy, Van der Hauwaert, Cynthia, Larrue, Romain, Lefebvre, Bruno, Van Seuningen, Isabelle, Cauffiez, Christelle, Pottier, Nicolas, and Perrais, Michaël
- Subjects
DISEASE progression ,RENAL cell carcinoma ,CANCER invasiveness ,ANTINEOPLASTIC agents ,CELL physiology ,RISK assessment ,CELL motility ,MOLECULAR biology ,TREATMENT effectiveness ,GLYCOPROTEINS ,CELL proliferation ,RESEARCH funding ,DRUG resistance in cancer cells ,PHARMACODYNAMICS - Abstract
Simple Summary: Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional systemic therapies and also to targeted therapies. Identifying the actors and deciphering the molecular mechanisms that lead to tumor progression and/or chemoresistance is an important step in developing new therapeutic strategies to cure ccRCC. In this context, we focused our attention on MUC1, a membrane-bound mucin, which is overexpressed in two-thirds of cancers and known to play a role in tumor progression, chemoresistance, and the establishment of an immunosuppressive microenvironment. In this study, we show that MUC1 overexpression increases the proliferation, invasion, and migration of ccRCC cells and is involved in mediating resistance to conventional and targeted therapies. Overall, our data suggest that MUC1 silencing may represent a potential therapeutic option for ccRCC. While the transmembrane glycoprotein mucin 1 (MUC1) is clustered at the apical borders of normal epithelial cells, with transformation and loss of polarity, MUC1 is found at high levels in the cytosol and is uniformly distributed over the entire surface of carcinoma cells, where it can promote tumor progression and adversely affects the response to therapy. Clear cell renal cell carcinoma (ccRCC), the main histotype of kidney cancer, is typically highly resistant to conventional and targeted therapies for reasons that remain largely unknown. In this context, we investigated whether MUC1 also plays a pivotal role in the cellular and molecular events driving ccRCC progression and chemoresistance. We showed, using loss- and gain-of-function approaches in ccRCC-derived cell lines, that MUC1 not only influences tumor progression but also induces a multi-drug-resistant profile reminiscent of the activation of ABC drug efflux transporters. Overall, our results suggest that targeting MUC1 may represent a novel therapeutic approach to limit ccRCC progression and improve drug sensitivity. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
14. A novel anti-galectin-9 immunotherapy limits the early progression of pancreatic neoplastic lesions in transgenic mice.
- Author
-
Quilbe, Alexandre, Mustapha, Rami, Duchêne, Belinda, Kumar, Abhishek, Werkmeister, Elisabeth, Leteurtre, Emmanuelle, Moralès, Olivier, Jonckheere, Nicolas, Van Seuningen, Isabelle, and Delhem, Nadira
- Subjects
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]
- Published
- 2023
- Full Text
- View/download PDF
15. Expression and function of Olfr78 and Olfr558 in the mouse gastrointestinal tract
- Author
-
Garcia, Marie-Isabelle, Parmentier, Marc, Moreno, Christophe, Pirson, Isabelle, Van Keymeulen, Alexandra, Laurent, Patrick, Depoortere, Inge, Van Seuningen, Isabelle IVS, Dinsart, Gilles, Garcia, Marie-Isabelle, Parmentier, Marc, Moreno, Christophe, Pirson, Isabelle, Van Keymeulen, Alexandra, Laurent, Patrick, Depoortere, Inge, Van Seuningen, Isabelle IVS, and Dinsart, Gilles
- Abstract
Les récepteurs olfactifs (OR) constituent la plus grande famille de récepteurs couplés aux protéines G (RCPG). L'intérêt croissant pour l'étude de ces récepteurs en dehors de la sphère olfactive a apporté des informations concernant l'expression des OR et leurs fonctions potentielles dans plusieurs tissus, tels que la peau, le cœur ou l'intestin. Au départ de ce projet, deux OR particuliers, nommés OR51E1/Olfr558 et OR51E2/Olfr78 (orthologues humain/souris), avaient été montrés comme étant exprimés dans certains sous-types de cellules entéroendocrines (EEC) de l’intestin. Les EEC jouent un rôle majeur dans la régulation du métabolisme global et de l’homéostasie intestinale grâce à la sécrétion d’hormones telles que GLP-1, PYY, ou encore la sérotonine aussi nommée 5-Hydroxytryptamine (5-HT). Il a été proposé que ces deux ORs, répondant aux acides gras à chaîne courte produits massivement par le microbiote intestinal, seraient impliqués dans la sécrétion des hormones EEC. Afin de mieux comprendre le rôle biologique potentiel de ces deux ORs dans l’intestin murin, nous avons d’abord étudié le profil d'expression complet de ces récepteurs le long du tractus digestif, en particulier celui de Olfr78. Nous avons montré que leur expression était principalement restreinte aux cellules épithéliales et mésenchymateuses du côlon. Ensuite, grâce à l’utilisation de la lignée murine transgénique rapportrice Olfr78-GFP dite « knock-in/knock-out » pour le récepteur Olfr78, nous avons pu étudier le profil transcriptomique des cellules épithéliales coliques exprimant Olfr78 et avons montré qu'il s’agit de cellules neuroendocrines de deux sous-types de EEC :les cellules L capables de produire du GLP-1 et du PYY et les cellules entérochromaffines (EC) sécrétant 5-HT. Ces dernières cellules sont enrichies en marqueurs présynaptiques et coexpriment l’OR Olfr558. En outre, nous avons démontré que la différenciation terminale des cellules EC, mais pas celle des cellules L, était déficiente, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished
- Published
- 2023
16. Metabolism of pancreatic neuroendocrine tumors: what can omics tell us?
- Author
-
Jannin, Arnaud, Dessein, Anne-Frédérique, Do Cao, Christine, Vantyghem, Marie-Christine, Chevalier, Benjamin, Van Seuningen, Isabelle, Jonckheere, Nicolas, and Coppin, Lucie
- Subjects
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]
- Published
- 2023
- Full Text
- View/download PDF
17. Cryosectioning the intestinal crypt-villus axis: An ex vivo method to study the dynamics of epigenetic modifications from stem cells to differentiated cells
- Author
-
Vincent, Audrey, Kazmierczak, Catherine, Duchêne, Belinda, Jonckheere, Nicolas, Leteurtre, Emmanuelle, and Van Seuningen, Isabelle
- Published
- 2015
- Full Text
- View/download PDF
18. 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
- Author
-
Jonckheere, Nicolas and Van Seuningen, Isabelle
- Published
- 2018
- Full Text
- View/download PDF
19. Hemidesmosome integrity protects the colon against colitis and colorectal cancer
- Author
-
De Arcangelis, Adèle, Hamade, Hussein, Alpy, Fabien, Normand, Sylvain, Bruyère, Emilie, Lefebvre, Olivier, Méchine-Neuville, Agnès, Siebert, Stéphanie, Pfister, Véronique, Lepage, Patricia, Laquerriere, Patrice, Dembele, Doulaye, Delanoye-Crespin, Anne, Rodius, Sophie, Robine, Sylvie, Kedinger, Michèle, Van Seuningen, Isabelle, Simon-Assmann, Patricia, Chamaillard, Mathias, Labouesse, Michel, and Georges-Labouesse, Elisabeth
- Published
- 2017
- Full Text
- View/download PDF
20. Neurotrophins promotes brain metastasis of triple negative breast cancer through Src kinase family activation
- Author
-
Cicero, Julien, Trouvilliez, Sarah, Palma, Martine, Ternier, Gaetan, Decoster, Laurine, Barrois, Nicolas, Dehouck, Lucie, Happernegg, Eloise, Bourette, Roland, Adriaenssens, Eric, Lagadec, Chann, Tarhan, Mehmet, Collard, Dominique, Souguir, Zied, Vandenhaute, Elodie, Maubon, Grégory, Maubon, Nathalie, SIPIETER, FRANCOIS, Sipieter, François, Borghi, Nicolas, Giacobini, Paolo, Prevost, Vincent, Gosselet, Fabien, Le Bourhis, Xuefen, van Seuningen, Isabelle, Mysiorek, Caroline, Toillon, Robert-Alain, IEMN, Collection, 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), Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Bio-Micro-Electro-Mechanical Systems - IEMN (BIOMEMS - IEMN), Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), JUNIA (JUNIA), Université catholique de Lille (UCL), Laboratory for Integrated Micro Mechatronics Systems (LIMMS), The University of Tokyo (UTokyo)-Centre National de la Recherche Scientifique (CNRS), HCS-Pharma Loos [Lille] (HCS-PL), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
[SPI]Engineering Sciences [physics] ,[SPI] Engineering Sciences [physics] - Abstract
ORAL; International audience; With nearly 2.3 million cases diagnosed worldwide each year and an estimated 685 000 deaths by 2020, breast cancer is the leading cause of cancer-related death in women. Brain metastases cause severe cognitive complications that severely impair quality of life. In TN breast cancer, the prognosis for brain metastases is particularly poor with a median survival of no more than 6 months. It is therefore crucial to know the molecular actors that promote the metastatic dissemination of triple negative breast cancer to the brain but also to prevent the proliferation of brain micrometastases that can cause fatal recurrences. In order to recapitulate several final stages of brain metastasis, we used both human Blood- Brain-Barrier in vitro model, human organotypic 3D extracellular in vitro matrix, mice brain slices organotypic ex vivo culture and in vivo mice xenograft. These models are coupled with single cell, 3D and real time imaging techniques, including FRET biosensing. This unique experimental approach allows us to study the involvement of signaling pathways in these different biological processes. Using this innovative method, we have identified that inhibition neurotrophins receptor leads to a decrease in the activity of the underlying signaling pathways and consequently to a decrease in the ability of breast cancer cells to pass through the BBB, to grow and to colonize the brain parenchyma.
- Published
- 2022
21. Galectin-3 is a non-classic RNA binding protein that stabilizes the mucin MUC4 mRNA in the cytoplasm of cancer cells
- Author
-
Coppin, Lucie, Vincent, Audrey, Frénois, Frédéric, Duchêne, Belinda, Lahdaoui, Fatima, Stechly, Laurence, Renaud, Florence, Villenet, Céline, Van Seuningen, Isabelle, Leteurtre, Emmanuelle, Dion, Johann, Grandjean, Cyrille, Poirier, Françoise, Figeac, Martin, Delacour, Delphine, Porchet, Nicole, and Pigny, Pascal
- Published
- 2017
- Full Text
- View/download PDF
22. Analysis of the proximal promoter of the human colon-specific B4GALNT2 (Sda synthase) gene: B4GALNT2 is transcriptionally regulated by ETS1
- Author
-
Wavelet-Vermuse, Cindy, Groux-Degroote, Sophie, Vicogne, Dorothée, Cogez, Virginie, Venturi, Giulia, Trinchera, Marco, Brysbaert, Guillaume, Krzewinski-Recchi, Marie-Ange, Bachir, Elsa Hadj, Schulz, Céline, Vincent, Audrey, Van Seuningen, Isabelle, Harduin-Lepers, Anne, 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), Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Universitá degli Studi dell’Insubria, This work was supported in part by the Centre National de la Recherche Scientifique (CNRS), the University of Lille. La Ligue contre le cancer (2016) and the Agence Nationale de la Recherche (ANR) financial support (ANR-2010-BLAN-120401) are acknowledged., ANR-10-BLAN-1204,GALFISH,Régulation moléculaire et cellulaire de la beta1,4-GalNAcT-II dans les états physiologiques et pathologiques (cancers gastrointestinaux)(2010), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Harduin-Lepers, Anne, and BLANC - Régulation moléculaire et cellulaire de la beta1,4-GalNAcT-II dans les états physiologiques et pathologiques (cancers gastrointestinaux) - - GALFISH2010 - ANR-10-BLAN-1204 - BLANC - VALID
- Subjects
Transcriptional regulation ,ETS1 ,Colon ,[SDV]Life Sciences [q-bio] ,B4GALNT2 ,Core promoter ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience; Background: The Sda antigen and corresponding biosynthetic enzyme B4GALNT2 are primarily expressed in normal colonic mucosa and are down-regulated to a variable degree in colon cancer tissues. Although their expression profile is well studied, little is known about the underlying regulatory mechanisms. Methods: To clarify the molecular basis of Sda expression in the human gastrointestinal tract, we investigated the transcriptional regulation of the human B4GALNT2 gene. The proximal promoter region was delineated using luciferase assays and essential trans-acting factors were identified through transient overexpression and silencing of several transcription factors. Results: A short cis-regulatory region restricted to the −72 to +12 area upstream of the B4GALNT2 short-type transcript variant contained the essential promoter activity that drives the expression of the human B4GALNT2 regardless of the cell type. We further showed that B4GALNT2 transcriptional activation mostly requires ETS1 and to a lesser extent SP1. Conclusions: Results presented herein are expected to provide clues to better understand B4GALNT2 regulatory mechanisms.
- Published
- 2021
23. The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential
- Author
-
Renaud, Florence, Mariette, Christophe, Vincent, Audrey, Wacrenier, Agnès, Maunoury, Vincent, Leclerc, Julie, Coppin, Lucie, Crépin, Michel, Van Seuningen, Isabelle, Leteurtre, Emmanuelle, and Buisine, Marie-Pierre
- Published
- 2016
- Full Text
- View/download PDF
24. MUC5AC hypomethylation is a predictor of microsatellite instability independently of clinical factors associated with colorectal cancer
- Author
-
Renaud, Florence, Vincent, Audrey, Mariette, Christophe, Crépin, Michel, Stechly, Laurence, Truant, Stéphanie, Copin, Marie-Christine, Porchet, Nicole, Leteurtre, Emmanuelle, Van Seuningen, Isabelle, and Buisine, Marie-Pierre
- Published
- 2015
- Full Text
- View/download PDF
25. Overexpression of chemokine receptor CXCR2 and ligand CXCL7 in liver metastases from colon cancer is correlated to shorter disease-free and overall survival
- Author
-
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
- Published
- 2015
- Full Text
- View/download PDF
26. TRPM7 Modulates Human Pancreatic Stellate Cell Activation.
- Author
-
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
- Subjects
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]
- Published
- 2022
- Full Text
- View/download PDF
27. Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer
- Author
-
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
- Subjects
[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.
- Published
- 2018
28. 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
- Author
-
Jonckheere, Nicolas and Seuningen, Isabelle Van
- Subjects
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 ).
- Published
- 2018
- Full Text
- View/download PDF
29. Gemcitabine‐induced epithelial‐mesenchymal transition‐like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal‐like phenotype.
- Author
-
El Amrani, Mehdi, Corfiotti, François, Corvaisier, Matthieu, Vasseur, Romain, Fulbert, Maxence, Skrzypczyk, Cécile, Deshorgues, Anne‐Claire, Gnemmi, Viviane, Tulasne, David, Lahdaoui, Fatima, Vincent, Audrey, Pruvot, François‐René, Seuningen, Isabelle, Huet, Guillemette, and Truant, Stéphanie
- Published
- 2019
- Full Text
- View/download PDF
30. Flagellin-mediated protection against intestinal Yersinia pseudotuberculosis infection does not require interleukin-22.
- Author
-
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.
- Published
- 2017
31. 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
- Author
-
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
- Subjects
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.
- Published
- 2015
32. EGF-Containing Membrane-Bound Mucins: A Hidden ErbB2 Targeting Pathway?
- Author
-
Liberelle, Maxime, Jonckheere, Nicolas, Melnyk, Patricia, Van Seuningen, Isabelle, and Lebègue, Nicolas
- Abstract
Membrane-bound mucins belong to a heterogeneous family of large O-glycoproteins involved in numerous cancers and inflammatory diseases of the epithelium. Some of them are also involved in protein–protein interactions, with receptor tyrosine kinase ErbB2, and fundamental and clinical data showed that these complexes have a detrimental impact on cancer outcome, thus raising interest in therapeutic targeting. This paper aims to demonstrate that MUC3, MUC4, MUC12, MUC13, and MUC17 have a common evolutionary origin and share a common structural organization with EGF-like and SEA domains. Theoretical structure–function relationship analysis of the conserved domains indicated that the studied membrane-bound mucins share common biological properties along with potential specific functions. Finally, the potential druggability of these complexes is discussed, revealing ErbB2-related pathways of cell signaling to be targeted.
- Published
- 2020
- Full Text
- View/download PDF
33. Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway.
- Author
-
Lahdaoui, Fatima, Messager, Mathieu, Vincent, Audrey, Hec, Flora, Gandon, Anne, Warlaumont, Maxime, Renaud, Florence, Leteurtre, Emmanuelle, Piessen, Guillaume, Jonckheere, Nicolas, Mariette, Christophe, and Van Seuningen, Isabelle
- Subjects
MUCINS ,TUMOR prognosis ,CANCER ,TUMOR growth ,CARCINOGENESIS - Abstract
Secreted mucins are large O-glycosylated proteins that participate in the protection/ defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to in vitro proliferation, migration and invasion, and in vivo on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT--PCR were used to identify proteins and signalling pathways involved. In vitro MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. In vivo xenografts of MUC5B-defi- cient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
34. Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.
- Author
-
Gaudelot, Kelly, Gibier, Jean-Baptiste, Pottier, Nicolas, Hémon, Brigitte, Van Seuningen, Isabelle, Glowacki, François, Leroy, Xavier, Cauffiez, Christelle, Gnemmi, Viviane, Aubert, Sébastien, and Perrais, Michaël
- Subjects
RENAL cell carcinoma ,CARCINOMA ,RENAL cancer ,MICRORNA ,CANCER invasiveness - Abstract
Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
35. 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.
- Author
-
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.)
- Published
- 2015
- Full Text
- View/download PDF
36. MUC5 AC hypomethylation is a predictor of microsatellite instability independently of clinical factors associated with colorectal cancer.
- Author
-
Renaud, Florence, Vincent, Audrey, Mariette, Christophe, Crépin, Michel, Stechly, Laurence, Truant, Stéphanie, Copin, Marie‐Christine, Porchet, Nicole, Leteurtre, Emmanuelle, Van Seuningen, Isabelle, and Buisine, Marie‐Pierre
- Abstract
Colorectal cancers (CRC) with microsatellite instability (MSI) display unique clinicopathologic features including a mucinous pattern with frequent expression of the secreted mucins MUC2 and MUC5AC. The mechanisms responsible for this altered pattern of expression remain largely unknown. We quantified DNA methylation of mucin genes ( MUC2, MUC5AC, MUC4) in colonic cancers and examined the association with clinicopathological characteristics and molecular (MSI, KRAS, BRAF, and TP53 mutations) features. A control cohort was used for validation. We detected frequent hypomethylation of MUC2 and MUC5AC in CRC. MUC2 and MUC5AC hypomethylation was associated with MUC2 and MUC5AC protein expression ( p = 0.004 and p < 0.001, respectively), poor differentiation ( p = 0.001 and p = 0.007, respectively) and MSI status ( p < 0.01 and p < 0.001, respectively). Interestingly, MUC5AC hypomethylation was specific to MSI cancers. Moreover, it was significantly associated with BRAF mutation and CpG island methylator phenotype ( p < 0.001 and p < 0.001, respectively). All these results were confirmed in the control cohort. In the multivariate analysis, MUC5AC hypomethylation was a highly predictive biomarker for MSI cancers. MUC5AC demethylation appears to be a hallmark of MSI in CRC. Determination of MUC5AC methylation status may be useful for understanding and predicting the natural history of CRC. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
37. Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma.
- Author
-
Boukrout, Nihad, Souidi, Mouloud, Lahdaoui, Fatima, Duchêne, Belinda, Neve, Bernadette, Coppin, Lucie, Leteurtre, Emmanuelle, Torrisani, Jérôme, Van Seuningen, Isabelle, and Jonckheere, Nicolas
- Subjects
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]
- Published
- 2021
- Full Text
- View/download PDF
38. Fabricating Silicon Resonators for Analysing Biological Samples.
- Author
-
Kumemura, Momoko, Pekin, Deniz, Menon, Vivek Anand, Van Seuningen, Isabelle, Collard, Dominique, and Tarhan, Mehmet Cagatay
- Subjects
RESONATORS ,MICROELECTROMECHANICAL systems ,MICROTECHNOLOGY ,ELECTROMECHANICAL technology ,ACTUATORS - Abstract
The adaptability of microscale devices allows microtechnologies to be used for a wide range of applications. Biology and medicine are among those fields that, in recent decades, have applied microtechnologies to achieve new and improved functionality. However, despite their ability to achieve assay sensitivities that rival or exceed conventional standards, silicon-based microelectromechanical systems remain underutilised for biological and biomedical applications. Although microelectromechanical resonators and actuators do not always exhibit optimal performance in liquid due to electrical double layer formation and high damping, these issues have been solved with some innovative fabrication processes or alternative experimental approaches. This paper focuses on several examples of silicon-based resonating devices with a brief look at their fundamental sensing elements and key fabrication steps, as well as current and potential biological/biomedical applications. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
39. The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis.
- Author
-
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
- Subjects
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
- Full Text
- View/download PDF
40. Loss of Polycomb Repressive Complex 2 Function Alters Digestive Organ Homeostasis and Neuronal Differentiation in Zebrafish.
- Author
-
Raby, Ludivine, Völkel, Pamela, Hasanpour, Shaghayegh, Cicero, Julien, Toillon, Robert-Alain, Adriaenssens, Eric, Van Seuningen, Isabelle, Le Bourhis, Xuefen, and Angrand, Pierre-Olivier
- Subjects
DIGESTIVE organs ,NEURONAL differentiation ,BRACHYDANIO ,FATTY liver ,HISTONE methylation ,PANCREAS - Abstract
Polycomb repressive complex 2 (PRC2) mediates histone H3K27me3 methylation and the stable transcriptional repression of a number of gene expression programs involved in the control of cellular identity during development and differentiation. Here, we report on the generation and on the characterization of a zebrafish line harboring a null allele of eed, a gene coding for an essential component of the PRC2. Homozygous eed-deficient mutants present a normal body plan development but display strong defects at the level of the digestive organs, such as reduced size of the pancreas, hepatic steatosis, and a loss of the intestinal structures, to die finally at around 10–12 days post fertilization. In addition, we found that PRC2 loss of function impairs neuronal differentiation in very specific and discrete areas of the brain and increases larval activity in locomotor assays. Our work highlights that zebrafish is a suited model to study human pathologies associated with PRC2 loss of function and H3K27me3 decrease. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
41. Magnesium transporters: Discovering new potential biomarkers in digestive cancers.
- Author
-
Auwercx, Julie, Rybarczyk, Pierre, Kischel, Philippe, Duthille, Isabelle Dhennin, Chatelain, Denis, Sevestre, Henri, Van Seuningen, Isabelle, Ouadid-Ahidouch, Halima, Jonckheere, Nicolas, and Gautier, Mathieu
- Subjects
TUMOR markers ,GENE expression ,OVERALL survival ,CANCER cell proliferation ,MEMBRANE transport proteins ,CELL migration - Abstract
Purpose: Many epidemiological studies suggest that a bad diet and lifestyle could increase the risk of developing digestive cancer [2-4]. Notably, magnesium (Mg
2+ ) intake decreases over the years and could be linked to the incidence of some digestive cancers such as pancreatic cancer [5]. Mg2+ is essential for cellular physiology, as it regulates a lot of cellular processes. Its homeostasis is regulated by membrane transporters, such as TRPM6, TRPM7, MAGT1, CNNM4, SLC41A1, and MRS2. However, their distribution in tissues from digestive cancers has not been exhaustively studied. This work aims to study Mg2+ transporter transporter expression in digestive cancers and their impact on patient survival. Materials and methods: We analyzed the Mg2+ transporters TRPM6, TRPM7, MAGT1, CNNM1-4, SLC41A1, and MRS2 mRNA relative expression from the TCGA transcriptomic datasets to investigate their expression pattern, combinatory correlation, and their impact on survival in esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), pancreatic adenocarcinoma (PAAD) and colorectal adenocarcinoma (COADREAD). Genotype Tissue Expression (GTEx) and Cancer Genome Atlas (TCGA) datasets were analyzed in this study, using GEPIA2 and RStudio tools. Results: By comparing nontumoral and tumoral tissues, we observed an alteration of Mg2+ transporters expression in most of digestive cancers. MAGT1 and CNNM4 are overexpressed in all digestive cancers and are negatively correlated with overall-survival and in disease-free in PAAD patients. High TRPM6 was correlated with a better outcome in those patients. Interestingly, we identified a gene signature involving MAGT1, CNNM4 and TRPM7. This signature is associated with poor prognosis in some digestive cancers, like PAAD, ESCA or COADREAD. Conclusion: Our work suggests the importance of Mg2+ transporters such as MAGT1, TRPM7, and CNNM4 as potential new biomarkers in digestive cancers. More analyses are required to evaluate the functional interaction among those proteins and their impact on cancer processes such as cell proliferation, migration, or invasion. [ABSTRACT FROM AUTHOR]- Published
- 2021
42. Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.
- Author
-
Linnekamp, Janneke F., Kandimalla, Raju, Fessler, Evelyn, de Jong, Joan H., Rodermond, Hans M., van Bochove, Gregor G. W., The, Frans O., Punt, Cornelis J. A., Bemelman, Willem A., van de Ven, Anthony W. H., Tanis, Pieter J., Kemper, Elles M., Koens, Lianne, Dekker, Evelien, Vermeulen, Louis, van Laarhoven, Hanneke W. M., Medema, Jan Paul, Baiocchi, Marta, Zeuner, Ann, and Seuningen, Isabelle Van
- Subjects
COLON tumors ,WNT proteins ,DECITABINE ,CANCER patients ,GENE expression ,TREATMENT effectiveness ,METHYLATION ,DESCRIPTIVE statistics ,GENES ,PREANESTHETIC medication ,PHARMACODYNAMICS - Abstract
Simple Summary: Colon cancer is one of the leading causes of cancer-related death worldwide. Therefore, the development of new therapeutic strategies is of the utmost importance. Previously, we identified a subset of colon cancers that are characterised by DNA methylation and have a poor prognosis. In this study, we therefore treated ten colon cancer patients with a demethylating agent, decitabine, to investigate if reversal of methylation is feasible and can be used as a novel therapy. Unfortunately, this study revealed that while decitabine treatment is effective in vitro, it only marginally decreased global methylation in patients and had no effect on the specific regions of DNA methylation in the tumours. Future studies should therefore focus on optimisation of treatment schedules in patients with highly methylated tumours. DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m
2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre- and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
43. The EGF domains of MUC4 oncomucin interact with ErbB2 and mediate tumorigenic activity of cancer cells represent new potential therapeutic targets.
- Author
-
Stoup, Nicolas, Liberelle, Maxime, Schulz, Céline, Vasseur, Romain, Magnez, Romain, Thuru, Xavier, Melnyk, Patricia, Renault, Nicolas, Jonckheere, Nicolas, Lebegue, Nicolas, and Van Seuningen, Isabelle
- Published
- 2021
- Full Text
- View/download PDF
44. A Drastic Shift in Lipid Adducts in Colon Cancer Detected by MALDI-IMS Exposes Alterations in Specific K + Channels.
- Author
-
Garate, Jone, Maimó-Barceló, Albert, Bestard-Escalas, Joan, Fernández, Roberto, Pérez-Romero, Karim, Martínez, Marco A., Payeras, Mª Antònia, Lopez, Daniel H., Fernández, José Andrés, Barceló-Coblijn, Gwendolyn, and Van Seuningen, Isabelle
- Subjects
COLON tumors ,HEMOSTASIS ,GENE expression ,MASS spectrometry ,CELL proliferation ,LIPID peroxidation (Biology) ,POTASSIUM antagonists ,PHARMACODYNAMICS - Abstract
Simple Summary: Colorectal cancer (CRC) is one of the most preventable yet deadliest cancers, one reason being that it involves very different lesions. Currently, there is a great international effort to improve CRC classification using as many molecular features as possible. A cutting-edge technique, imaging mass spectrometry, is used to enable the visualization of the bidimensional (2D) distribution of molecules across tissues in order to study how the composition of the cell membrane, in particular membrane lipids, changes in tumors. Our previous studies indicate that lipid composition is highly sensitive to cell alterations. Importantly, during the analysis, we are also able to establish changes in charged lipids, observations that can be misinterpreted. A close study of our results alongside information from public databases leads to the identification of gene coding for a potassium channel that could account for our observations and could represent a suitable target for drug development. Even though colorectal cancer (CRC) is one of the most preventable cancers, it is one of the deadliest, and recent data show that the incidence in people <50 years has unexpectedly increased. While new techniques for CRC molecular classification are emerging, no molecular feature is as yet firmly associated with prognosis. Imaging mass spectrometry (IMS) lipidomic analyses have demonstrated the specificity of the lipid fingerprint in differentiating pathological from healthy tissues. During IMS lipidomic analysis, the formation of ionic adducts is common. Of particular interest is the [Na
+ ]/[K+ ] adduct ratio, which already functions as a biomarker for homeostatic alterations. Herein, we show a drastic shift of the [Na+ ]/[K+ ] adduct ratio in adenomatous colon mucosa compared to healthy mucosa, suggesting a robust increase in K+ levels. Interrogating public databases, a strong association was found between poor diagnosis and voltage-gated potassium channel subunit beta-2 (KCNAB2) overexpression. We found this overexpression in three CRC molecular subtypes defined by the CRC Subtyping Consortium, making KCNAB2 an interesting pharmacological target. Consistently, its pharmacological inhibition resulted in a dramatic halt in commercial CRC cell proliferation. Identification of potential pharmacologic targets using lipid adduct information emphasizes the great potential of IMS lipidomic techniques in the clinical field. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
45. Mg 2+ Transporters in Digestive Cancers.
- Author
-
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
- Full Text
- View/download PDF
46. Unsupervised Hierarchical Clustering of Pancreatic Adenocarcinoma Dataset from TCGA Defines a Mucin Expression Profile that Impacts Overall Survival.
- Author
-
Jonckheere, Nicolas, Auwercx, Julie, Hadj Bachir, Elsa, Coppin, Lucie, Boukrout, Nihad, Vincent, Audrey, Neve, Bernadette, Gautier, Mathieu, Treviño, Victor, and Van Seuningen, Isabelle
- Subjects
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]
- Published
- 2020
- Full Text
- View/download PDF
47. Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia.
- Author
-
Lambert, Mélanie, Alioui, Meryem, Jambon, Samy, Depauw, Sabine, Seuningen, Isabelle Van, and David-Cordonnier, Marie-Hélène
- Subjects
GENE expression ,TRANSCRIPTION factors ,DNA-binding proteins ,FETAL development ,ACUTE myeloid leukemia ,HEMATOLOGIC malignancies ,EPIGENOMICS - Abstract
HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an "undruggable" target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
48. TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727.
- Author
-
Drubay, Vincent, Skrypek, Nicolas, Cordiez, Lucie, Vasseur, Romain, Schulz, Céline, Boukrout, Nihad, Duchêne, Belinda, Coppin, Lucie, Van Seuningen, Isabelle, and Jonckheere, Nicolas
- Subjects
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]
- Published
- 2018
- Full Text
- View/download PDF
49. Suitability of Surgically Induced Chronic Reflux in Rats for Studying Esophageal Carcinogenesis.
- Author
-
Gronnier, Caroline, Piessen, Guillaume, Leteurtre, Emmanuelle, Van Seuningen, Isabelle, and Mariette, Christophe
- Published
- 2015
- Full Text
- View/download PDF
50. Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosisInfection Does Not Require Interleukin-22
- Author
-
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
- Abstract
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.
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.