Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, PR China.
Section of Cancer Stem Cell Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, Xi'an, 710061, Shaanxi, PR China.
Oncogene. 2019 Oct;38(43):6940-6957. doi: 10.1038/s41388-019-0906-3. Epub 2019 Aug 13.
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 REX1 trans-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 by trans-suppressing SOCS1 expression.
ZFP42 锌指蛋白（REX1）是小鼠多能干细胞中的多能性标志物，已被确定为几种人类癌症中的肿瘤抑制因子。然而，REX1 在宫颈癌中的功能尚不清楚。免疫组织化学和 Western blot 检测均表明，宫颈癌组织中 REX1 蛋白的表达明显高于正常宫颈组织。异种移植实验表明，SiHa 和 HeLa 细胞中 REX1 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，REX1 的过表达还促进了体外细胞迁移和侵袭能力。在机制上，REX1 通过上调 VIMENTIN 和下调 E-CADHERIN 诱导上皮间质转化（EMT）。此外，REX1 过表达细胞中 JAK2/STAT3 信号通路被激活，表现为 p-STAT3 和 p-JAK2 水平升高，以及 JAK2/STAT3 信号通路抑制剂 SOCS1 的表达下调，在转录和翻译水平上均下调。双荧光素酶报告基因检测和 qChIP 检测证实，REX1 通过与 SOCS1 启动子的两个特定区域结合，反式抑制 SOCS1 的表达，从而反式抑制 SOCS1 的表达，从而抑制 SOCS1 的表达。因此，我们所有的数据表明，REX1 的过表达可能通过反式抑制 SOCS1 的表达而上调 JAK2/STAT3 通路的活性，在宫颈癌的转移和侵袭中发挥关键作用。
