STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion
STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion
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DOI：
10.1172/jci78173
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发表时间：
2015-04-01
影响因子：
15.9
通讯作者：
Melmed, Shlomo
中科院分区：
文献类型：
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作者：
Zhou, Cuiqi;Jiao, Yonghui;Melmed, Shlomo
垂体生长激素腺瘤导致生长激素（GH）分泌失调和肢端肥大症;然而，促进GH分泌过多的调节机制仍然难以捉摸。在这里，我们提供的证据表明，STAT 3直接诱导生长激素肿瘤细胞GH。垂体肿瘤的评估显示，STAT 3的表达增强，在人类生长激素分泌腺瘤相比，在非分泌垂体肿瘤。此外，生长激素腺瘤组织阵列中STAT 3和GH的表达是一致的。在GH分泌大鼠细胞系（GH 3）中的启动子和表达分析显示，STAT 3特异性结合Gh启动子并诱导转录。STAT 3在GH 3细胞中的稳定表达诱导内源性GH的表达，并且组成型活性STAT 3的表达进一步增强GH产生。相反，显性负性STAT 3的表达废除GH表达。在原代人生长激素腺瘤衍生的细胞培养物中，用特异性抑制剂S3 I-201抑制STAT 3减弱了GH转录，并减少了大多数衍生培养物中的GH分泌。此外，S3 I-201在大鼠异种移植模型中减弱促生长素肿瘤生长和GH分泌。CH诱导STAT 3磷酸化和核转位，表明生长激素肿瘤细胞中STAT 3和GH之间存在正反馈回路。总之，这些结果表明，腺瘤GH分泌过多是STAT 3依赖性GH诱导的结果，这反过来又促进STAT 3表达，并建议STAT 3作为垂体生长激素腺瘤的潜在治疗靶点。
Pituitary somatotroph adenomas result in dysregulated growth hormone (GH) hypersecretion and acromegaly; however, regulatory mechanisms that promote GH hypersecretion remain elusive. Here, we provide evidence that STAT3 directly induces somatotroph tumor cell GH. Evaluation of pituitary tumors revealed that STAT3 expression was enhanced in human GH-secreting adenomas compared with that in nonsecreting pituitary tumors. Moreover, STAT3 and GH expression were concordant in a somatotroph adenoma tissue array. Promoter and expression analysis in a GH-secreting rat cell line (GH3) revealed that STAT3 specifically binds the Gh promoter and induces transcription. Stable expression of STAT3 in GH3 cells induced expression of endogenous GH, and expression of a constitutively active STAT3 further enhanced GH production. Conversely, expression of dominant-negative STAT3 abrogated GH expression. In primary human somatotroph adenoma-derived cell cultures, STAT3 suppression with the specific inhibitor S3I-201 attenuated GH transcription and reduced GH secretion in the majority of derivative cultures. In addition, S3I-201 attenuated somatotroph tumor growth and GH secretion in a rat xenograft model. CH induced STAT3 phosphorylation and nuclear translocation, indicating a positive feedback loop between STAT3 and GH in somatotroph tumor cells. Together, these results indicate that adenoma GH hypersecretion is the result of STAT3-dependent GH induction, which in turn promotes STAT3 expression, and suggest STAT3 as a potential therapeutic target for pituitary somatotroph adenomas.