De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas

Autor: Laurent Sulpice, Cédric Coulouarn, Pascale Bellaud, Sihem Mebarki, Bruno Clément, Rémy Le Guével, Orlando Musso, Frédéric Canal, Bruno Turlin, Mireille Desille, Elise Lavergne, Marie Sicard, Hélène Dubois-Pot Schneider, Romain Desert, Anne Corlu, Christine Perret, Damien Bergeat
Přispěvatelé: Foie, métabolismes et cancer, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre de ressources biologiques de Rennes, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme ImPACcell ( ImPACcell ), Inserm,Université de Rennes 1, Région Bretagne, AgenceNationale de la Recherche, Institut National du Cancer,Fondation Recherche Médicale, Ligue Nationale Contrele Cancer (Comité des Côtes d’Armor), Feder, Contrat dePlan Etat Région 2007-2013, projet Cancéropôle., Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-forme ImPACcell (ImPACcell), Bos, Mireille, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Pathology
Ligands
Stem cell marker
Mesoderm
Research Paper: Gerotarget (Focus on Aging)
Cluster Analysis
CD44
Extracellular Matrix Proteins
biology
Gerotarget
Stem Cells
Liver Neoplasms
Wnt signaling pathway
LGR5
Cell Differentiation
Middle Aged
Immunohistochemistry
3. Good health
Gene Expression Regulation
Neoplastic
Liver
Oncology
Female
Proteoglycans
Hepatocyte dedifferentiation
Stem cell
Signal Transduction
medicine.medical_specialty
Carcinoma
Hepatocellular
epithelial-mesenchymal transition
Cell Line
Wnt
03 medical and health sciences
Cell Line
Tumor
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
medicine
Humans
Neoplasm Invasiveness
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Progenitor cell
[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Aged
Gene Expression Profiling
Fibroblasts
β-catenin
HCCS
Wnt Proteins
030104 developmental biology
Tissue Array Analysis
biology.protein
Cancer research
Follow-Up Studies
Zdroj: Oncotarget
Oncotarget, Impact journals, 2016, 7 (26), pp.39026--39043. 〈10.18632/oncotarget.9346〉
Oncotarget, 2016, 7 (26), pp.39026--39043. ⟨10.18632/oncotarget.9346⟩
Oncotarget, Impact journals, 2016, 7 (26), pp.39026--39043. ⟨10.18632/oncotarget.9346⟩
ISSN: 1949-2553
DOI: 10.18632/oncotarget.9346
Popis: International audience; About 20% hepatocellular carcinomas (HCCs) display wild-type β-catenin, enhanced Wnt signaling, hepatocyte dedifferentiation and bad outcome, suggesting a specific impact of Wnt signals on HCC stem/progenitor cells. To study Wnt-specific molecular pathways, cell fates and clinical outcome, we fine-tuned Wnt/β-catenin signaling in liver progenitor cells, using the prototypical Wnt ligand Wnt3a. Cell biology assays and transcriptomic profiling were performed in HepaRG hepatic progenitors exposed to Wnt3a after β-catenin knockdown or Wnt inhibition with FZD8_CRD. Gene expression network, molecular pathology and survival analyses were performed on HCCs and matching non-tumor livers from 70 patients by real-time PCR and tissue micro-array-based immunohistochemistry. Wnt3a reprogrammed liver progenitors to replicating fibrogenic myofibroblast-like cells displaying stem and invasive features. Invasion was inhibited by 30 nM FZD7 and FZD8 CRDs. Translation of these data to human HCCs revealed two tight gene networks associating cell surface Wnt signaling, stem/progenitor markers and mesenchymal commitment. Both networks were linked by Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1), that appeared de novo in aggressive HCCs expressing cytoplasmic β-catenin and stem cell markers. HAPLN1 was independently associated with bad overall and disease-free outcome. In vitro, HAPLN1 was expressed de novo in EPCAM¯/NCAM+ mesoderm-committed progenitors, upon spontaneous epithelial-mesenchymal transition and de-differentiation of hepatocyte-like cells to liver progenitors. In these cells, HAPLN1 knockdown downregulated key markers of mesenchymal cells, such as Snail, LGR5, collagen IV and α-SMA. In conclusion, HAPLN1 reflects a signaling network leading to stemness, mesenchymal commitment and HCC progression.
Databáze: OpenAIRE
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