Abstract
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.
Highlights
Cervical cancer is the fourth most commonly diagnosed cancer worldwide and the second leading cause of cancerrelated death among women in developing countries [1].These authors contributed : Yu-Ting Zeng and Xiao-Fang Liu
The expression level of REX1 was detected by western blotting in seven NC tissue samples and Immunocytochemical assays and western blot analyses were performed in cervical cancer cell lines
All of these results indicate that REX1 overexpression promotes the migration and invasion, as well as the metastasis of cervical cancer cells, possibly by regulating classical epithelial-to-mesenchymal transition (EMT)-related genes, including MMP9, VIMENTIN, and E-CADHERIN
Summary
Cervical cancer is the fourth most commonly diagnosed cancer worldwide and the second leading cause of cancerrelated death among women in developing countries [1]. We are the first to reveal that REX1 could facilitate the migration and invasion of cervical cancer cells in vitro and distant tumor metastasis in vivo by activating the JAK2/STAT3-signaling pathway in cervical cancer through trans-suppressing the expression of suppressor of cytokine signaling 1 (SOCS1). We analyzed REX1 expression in 304 patients with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) including 260 SCC, 22 endocervical type of adenocarcinoma, 15 mucinous adenocarcinoma of endocervical type, and 7 adenosquamous in The Cancer Genome Atlas (TCGA) RNAseq database. Survival analysis of the correlation between REX1 expression and overall survival probability of CESC patients, as assessed by Kaplan–Meier estimator, showed that as REX1 expression increased, the probability of CESC patient survival decreased (Fig. 1g, p = 0.011) All of these results suggest that REX1 might function as a promoter of cervical carcinogenesis and development
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