title: Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas.
abstract: 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.
authors.affiliation: Génomique fonctionnelle des tumeurs solides, Institut National de la Santé et de la Recherche Médicale (Inserm), U674, Paris, F-75010, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.forename: Mohamed
authors.initials: M
authors.lastname: Amessou
authors.forename: Michel P
authors.initials: MP
authors.lastname: Bihl
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Jeanne Tran Van
authors.initials: JT
authors.lastname: Nhieu
authors.forename: Valérie
authors.initials: V
authors.lastname: Paradis
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Nault
authors.forename: Tina
authors.initials: T
authors.lastname: Izard
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.forename: Karine
authors.initials: K
authors.lastname: Poussin
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D021581:Active Transport, Cell Nucleus; D018248:Adenoma, Liver Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D019281:Dimerization; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D020836:Protein Structure, Quaternary; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; C508600:IL6 protein, human; C494199:IL6ST protein, human; D015850:Interleukin-6; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D014443:Tyrosine; D019061:src-Family Kinases