1. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. : Activating STAT3 mutations in hepatocellular adenoma
- Author
-
Jeanne Tran Van Nhieu, Michel Bihl, Karine Poussin, Mohamed Amessou, Paulette Bioulac-Sage, Jessica Zucman-Rossi, Charles Balabaud, Camilla Pilati, Jean-Charles Nault, Tina Izard, Valérie Paradis, Gabrielle Couchy, Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Labex Immuno-oncology, Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Pathologie [Clichy], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Department of Cancer Biology, The Scripps Research Institute, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and This work was supported by the association pour la recherche Contre le Cancer (ARC, grant n°3194), Inserm (Réseaux de recherche clinique et réseaux de recherche en santé des populations), Collection Nationale des Carcinomes Hépatocellulaires, the Ligue Nationale Contre le Cancer ('Cartes d'identité des tumeurs' program) and the BioIntelligence collaborative program. C.P., M.A. and J-C.N. are supported by a fellowship from the MENRT, Inca and ARC, respectively. T.I. is supported by the National Institutes of Health grants GM071596, AI055894, and AI067949.
- Subjects
MESH : Tyrosine ,Male ,Models, Molecular ,MESH : Liver Neoplasms ,MESH : Mutant Proteins ,MESH : Aged ,MESH : RNA, Small Interfering ,SH2 domain ,medicine.disease_cause ,HNF1A ,STAT3 ,MESH : Phosphorylation ,0302 clinical medicine ,MESH : STAT3 Transcription Factor ,Cytokine Receptor gp130 ,Immunology and Allergy ,CTNNB1 ,MESH : Female ,SOCS3 ,Phosphorylation ,RNA, Small Interfering ,0303 health sciences ,Mutation ,Liver Neoplasms ,DNA, Neoplasm ,MESH : Adult ,Middle Aged ,SAA ,3. Good health ,MESH : Cytokine Receptor gp130 ,JAK1 ,src-Family Kinases ,JAK2 ,MESH : Dimerization ,030220 oncology & carcinogenesis ,[ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Female ,MESH : DNA, Neoplasm ,MESH : Mutation ,CRP ,IL6ST ,Dimerization ,Tyrosine kinase ,Src ,Signal Transduction ,Proto-oncogene tyrosine-protein kinase Src ,MESH : Carcinoma, Hepatocellular ,Adult ,STAT3 Transcription Factor ,Carcinoma, Hepatocellular ,MESH : Interleukin-6 ,MESH : Models, Molecular ,MESH : Male ,Immunology ,Active Transport, Cell Nucleus ,Biology ,IFN ,Adenoma, Liver Cell ,gp130 ,03 medical and health sciences ,MESH : Adenoma, Liver Cell ,MESH : Protein Structure, Quaternary ,Cell Line, Tumor ,medicine ,Humans ,MESH : Middle Aged ,Protein Structure, Quaternary ,MESH : Active Transport, Cell Nucleus ,Aged ,030304 developmental biology ,MESH : Signal Transduction ,IL-6 ,Base Sequence ,MESH : Cell Line, Tumor ,Interleukin-6 ,MESH : Humans ,Brief Definitive Report ,beta-catenin ,digestive system diseases ,STAT protein ,Inflammatory Hepatocellular Adenoma ,Cancer research ,Tyrosine ,MESH : src-Family Kinases ,MESH : Base Sequence ,Mutant Proteins ,Carcinogenesis - Abstract
Somatic STAT3 mutations present in a subset of inflammatory hepatocellular adenomas result in the generation of constitutively active STAT3 proteins that homodimerize independently of IL-6 stimulation., Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.
- Published
- 2011
- Full Text
- View/download PDF