STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis.
STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis.
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DOI：
10.1101/gad.311852.118
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发表时间：
2018-09-01
影响因子：
10.5
通讯作者：
Reich NC
中科院分区：
文献类型：
--
作者：
D'Amico S;Shi J;Martin BL;Crawford HC;Petrenko O;Reich NC
D'Amico等人表明，STAT3的缺失优先与间充质样表型的获得和更具侵袭性的肿瘤行为相关。关于信号转导子和转录激活子3（STAT 3）在癌症中的作用存在二分法。功能和遗传研究表明STAT3的内在需求或对常见类型癌症的抑制作用。STAT3的这些对比动作暗示了上下文依赖性。为了研究STAT3在癌症中功能的机制，我们评估了STAT3活性在KRAS驱动的肺癌和胰腺癌中的影响。我们的研究定义了STAT3在维持上皮细胞身份和分化中的一个基本的和以前未被认识的功能。STAT3的缺失优先与间充质样表型的获得和更具侵袭性的肿瘤行为相关。相反，通过Tyr705磷酸化的持续STAT3活化赋予影响致瘤潜力的分化的上皮形态。我们的研究结果暗示了一种机制，与其他激活模式相比，STAT3 Tyr705磷酸化的定量差异在肿瘤进展中直接导致离散结果。
D'Amico et al. show that loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior. A dichotomy exists regarding the role of signal transducer and activator of transcription 3 (STAT3) in cancer. Functional and genetic studies demonstrate either an intrinsic requirement for STAT3 or a suppressive effect on common types of cancer. These contrasting actions of STAT3 imply context dependency. To examine mechanisms that underlie STAT3 function in cancer, we evaluated the impact of STAT3 activity in KRAS-driven lung and pancreatic cancer. Our study defines a fundamental and previously unrecognized function of STAT3 in the maintenance of epithelial cell identity and differentiation. Loss of STAT3 preferentially associates with the acquisition of mesenchymal-like phenotypes and more aggressive tumor behavior. In contrast, persistent STAT3 activation through Tyr705 phosphorylation confers a differentiated epithelial morphology that impacts tumorigenic potential. Our results imply a mechanism in which quantitative differences of STAT3 Tyr705 phosphorylation, as compared with other activation modes, direct discrete outcomes in tumor progression.
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