STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence
STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence
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DOI：
10.1080/15384101.2016.1259037
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Jackson, Mark W.
中科院分区：
文献类型：
--
作者：
Bryson, Benjamin L.;Junk, Damian J.;Jackson, Mark W.
发展中的肿瘤微环境（TME）中的细胞因子可以驱动转化和随后的转移进展。乳腺TME中白细胞介素-6（IL-6）家族细胞因子抑瘤素M（OSM）水平升高与侵袭性、转移性癌症、肿瘤复发增加和患者预后不良相关。特别地，OSM在正常和非转化的人乳腺上皮细胞（HMEC）中参与肿瘤抑制性、信号转导和转录激活因子3（STAT 3）依赖性衰老反应。在这里，我们确定了一个新的联系之间的OSM激活的STAT 3信号和转化生长因子-β（TGF-β）信号通路，参与衰老的HMEC。通过表达显性负性TGF-β受体、用TGF-β受体抑制剂处理或使用SMAD 3-shRNA抑制SMAD 3表达来抑制功能性TGF-β/SMAD信号传导防止了OSM诱导的衰老。OSM促进涉及活化的STAT 3和SMAD 3的蛋白复合物，诱导SMAD 3的核定位，并增强SMAD 3介导的负责衰老的转录。相比之下，MYC（c-MYC）从组成型启动子的表达废除衰老和惊人的，与OSM合作，以促进转化表型，上皮间质转化（EMT），和侵袭性。我们的研究结果表明，一种新的STAT 3/SMAD 3信号轴是OSM介导的衰老所必需的，该衰老在转化过程中被选择以赋予侵袭性癌细胞特性。了解发展中的癌细胞如何绕过OSM/STAT 3/SMAD 3介导的衰老可能有助于确定未来“促衰老”疗法的新靶点，旨在重新参与这种隐藏的肿瘤抑制反应。
Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-beta (TGF-beta) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-beta/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-beta receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSM-induced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.