Génomique fonctionnelle des tumeurs solides, Institut National de la Santé et de la Recherche Médicale (Inserm), U674, Paris, F-75010, France.
J Exp Med. 2011 Jul 4;208(7):1359-66. doi: 10.1084/jem.20110283. Epub 2011 Jun 20.
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.
炎性肝细胞腺瘤（IHCAs）是良性肝肿瘤。这些肿瘤中有 60%具有白细胞介素 6 信号转导物（IL6ST；gp130）突变，可激活白细胞介素 6（IL-6）信号。在这里，我们报告说，缺乏 IL6ST 突变的 IHCA 亚组中有 12%携带有体细胞信号转导子和转录激活子 3（STAT3）突变（6/49）。这些突变大多数是在指导 STAT3 二聚化的 SH2 结构域中的氨基酸取代。与野生型 STAT3 不同，IHCA STAT3 突变体在肝细胞中独立于配体持续激活 IL-6 信号通路。事实上，IHCA STAT3 Y640 突变体独立于 IL-6 同源二聚化，并且对 IL-6 刺激过度敏感。这与酪氨酸 705 的磷酸化有关，酪氨酸 705 是 IL-6 诱导的 STAT3 激活所必需的残基。沉默或抑制磷酸化 STAT3 的酪氨酸激酶 JAK1 或 Src，会损害肝细胞中 IHCA STAT3 突变体的组成性活性。因此，我们首次在人类肿瘤中鉴定出了体细胞 STAT3 突变，揭示了 STAT3 反复激活的新机制，并强调了 IL-6-STAT3 通路在良性肝细胞肿瘤发生中的作用。
