REX1 promotes EMT-induced cell metastasis by activating the JAK2/STAT3-signaling pathway by targeting SOCS1 in cervical cancer
REX1 promotes EMT-induced cell metastasis by activating the JAK2/STAT3-signaling pathway by targeting SOCS1 in cervical cancer
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REX1 通过靶向宫颈癌中的 SOCS1 激活 JAK2/STAT3 信号通路，促进 EMT 诱导的细胞转移
DOI：
10.1038/s41388-019-0906-3
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发表时间：
2019-10-24
期刊：
影响因子：
8
通讯作者：
Zheng, Peng-Sheng
中科院分区：
文献类型：
--
作者：
Zeng, Yu-Ting;Liu, Xiao-Fang;Zheng, Peng-Sheng
ZFP 42锌指蛋白（REX 1）是小鼠多能干细胞中的多能性标志物，已被鉴定为几种人类癌症的肿瘤抑制因子。然而，REX 1在宫颈癌中的功能仍然未知。免疫组化和western blot检测均显示REX 1蛋白在宫颈癌组织中的表达明显高于正常宫颈组织。异种移植试验表明，REX 1在SiHa和HeLa细胞中的过表达促进了远处转移，但对体内肿瘤形成没有显著影响。此外，REX 1还促进了体外细胞迁移和侵袭能力。从机制上讲，REX 1过表达通过上调波形蛋白和下调E-钙粘蛋白诱导上皮向间充质转化（EMT）。此外，JAK 2/STAT 3信号通路在REX 1过表达细胞中被激活，这也表现出p-STAT 3和p-JAK 2水平的增加，以及SOCS 1表达的下调，SOCS 1是JAK 2/STAT 3信号通路的抑制剂，在转录和翻译水平上。双荧光素酶报告基因检测和qChIP检测证实，REX 1通过与SOCS 1启动子的两个特定区域结合来反式抑制SOCS 1的表达。因此，我们的所有数据表明，REX 1过表达可能通过反式抑制SOCS 1表达上调JAK 2/STAT 3通路的活性，在宫颈癌的转移和侵袭中发挥关键作用。
ZFP42 zinc finger protein (REX1), a pluripotency marker in mouse pluripotent stem cells, has been identified as a tumor suppressor in several human cancers. However, the function of REX1 in cervical cancer remains unknown. Both IHC and western blot assays demonstrated that the expression of REX1 protein in cervical cancer tissue was much higher than that in normal cervical tissue. A xenograft assay showed that REX1 overexpression in SiHa and HeLa cells facilitated distant metastasis but did not significantly affect tumor formation in vivo. In addition, in vitro cell migration and invasion capabilities were also promoted by REX1. Mechanistically, REX1 overexpression induced epithelial-to-mesenchymal transition (EMT) by upregulating VIMENTIN and downregulating E-CADHERIN. Furthermore, the JAK2/STAT3-signaling pathway was activated in REX1-overexpressing cells, which also exhibited increased levels of p-STAT3 and p-JAK2, as well as downregulated expression of SOCS1, which is an inhibitor of the JAK2/STAT3-signaling pathway, at both the transcriptional and translational levels. A dual-luciferase reporter assay and qChIP assays confirmed that REX1trans-suppressed the expression of SOCS1 by binding to two specific regions of the SOCS1 promoter. Therefore, all our data suggest that REX1 overexpression could play a crucial role in the metastasis and invasion of cervical cancer by upregulating the activity of the JAK2/STAT3 pathway bytrans-suppressing SOCS1 expression.