Liggins Institute, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand.
Endocrinology. 2010 Sep;151(9):4133-45. doi: 10.1210/en.2010-0273. Epub 2010 Jul 28.
We herein demonstrate an oncogenic role for signal transducer and activator of transcription (STAT)-3alpha (the full length STAT3 isoform), which also mediates autocrine human GH (hGH)-stimulated oncogenicity, in human endometrial carcinoma (EC) cells. Autocrine hGH stimulated Y705 phosphorylation of STAT3 and STAT3-mediated transcriptional activity in a SRC and Janus-2 Kinase dependent manner in human EC cell lines. Forced expression of a constitutively active variant of STAT3alpha increased proliferation, anchorage-independent, three-dimensional (3D) Matrigel, and xenograft growth and promoted epithelial-mesenchymal transition, migration, and invasion of EC cells. Conversely, the oncogenic capacity of EC cells was significantly impaired by treatment with JSI-124, an inhibitor of STAT3 phosphorylation and activity, small interfering RNA-mediated depletion of STAT3alpha, or a dominant-negative variant of STAT3alpha. Furthermore, the enhanced EC cell oncogenicity stimulated by autocrine hGH, was also abrogated by functional inhibition or small interfering RNA-mediated depletion of STAT3alpha. STAT3alpha may therefore be a common mediator of oncogenic signaling pathways stimulating progression of EC.
我们在此证明信号转导和转录激活因子（STAT）-3α（全长 STAT3 异构体）在人类子宫内膜癌（EC）细胞中具有致癌作用，它也介导自分泌的人 GH（hGH）刺激的致癌性。自分泌的 hGH 以 SRC 和 Janus-2 激酶依赖的方式刺激人类 EC 细胞系中 STAT3 的 Y705 磷酸化和 STAT3 介导的转录活性。组成性激活的 STAT3α变体的强制表达增加了增殖、锚定非依赖性三维（3D）Matrigel 和异种移植物生长，并促进了 EC 细胞的上皮-间充质转化、迁移和侵袭。相反，用 JSI-124（一种磷酸化和活性 STAT3 的抑制剂）、STAT3α 的小干扰 RNA 介导的耗竭或 STAT3α 的显性负变体处理，显著削弱了 EC 细胞的致癌能力。此外，自分泌 hGH 刺激的增强的 EC 细胞致癌性也被 STAT3α 的功能抑制或小干扰 RNA 介导的耗竭所消除。因此，STAT3α 可能是刺激 EC 进展的致癌信号通路的共同介质。
