The novel ZIP4 regulation and its role in ovarian cancer
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Qipeng Fan1, Qingchun Cai1, Pengfei Li1,2, Wenyan Wang1,3, Jing Wang1,4, Emily Gerry5, Tian-Li Wang5, Ie-Ming Shih5, Kenneth P. Nephew6 and Yan Xu1
1Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2Pharmaceutical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, P.R. China
3Department of Obstetrics and Gynecology, The Second Hospital of Anhui Medical University, Hefei City, 230601, P.R. China
4MASDINO (Beijing) Medical Research Co. Ltd., Beijing, 100123, P.R. China
5Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA
6Medical Sciences, Indiana University School of Medicine, Jordan Hall 302, Bloomington, IN 47405, USA
Yan Xu, email: [email protected]
Keywords: ZIP4, LPA, ovarian cancer, cancer stem cells (CSC)
Received: June 07, 2017 Accepted: August 26, 2017 Published: September 30, 2017
Our RNAseq analyses revealed that ZIP4 is a top gene up-regulated in more aggressive ovarian cancer cells. ZIP4’s role in cancer stem cells has not been reported in any type of cancer. In addition, the role and regulation of ZIP4, a zinc transporter, have been studied in the context of extracellular zinc transporting. Factors other than zinc with ZIP4 regulatory effects are essentially unknown. ZIP4 expression and its regulation in epithelial ovarian cancer cells was assessed by immunoblotting, quantitative PCR, or immunohistochemistry staining in human ovarian tissues. Cancer stem cell-related activities were examined to evaluate the role of ZIP4 in human high-grade serous ovarian cancer cells in vitro and in vivo. RNAi and CRISPR techniques were used to knockdown or knockout ZIP4 and related genes. Ovarian cancer tissues overexpressed ZIP4 when compared with normal and benign tissues. ZIP4 knockout significantly reduced several cancer stem cell-related activities in EOC cells, including proliferation, anoikis-resistance, colony-formation, spheroid-formation, drug-resistance, and side-population in vitro. ZIP4-expressing side-population highly expressed known CSC markers ALDH1 and OCT4. ZIP4 knockout dramatically reduced tumorigenesis and ZIP4 overexpression increased tumorigenesis in vivo. In addition, the ZIP4-expressing side-population had the tumor initiating activity. Moreover, the oncolipid lysophosphatic acid effectively up-regulated ZIP4 expression via the nuclear receptor peroxisome proliferator-activated receptor gamma and lysophosphatic acid ’s promoting effects in cancer stem cell-related activities in HGSOC cells was at least partially mediated by ZIP4 in an extracellular zinc-independent manner. Our critical data imply that ZIP4 is a new and important cancer stem cell regulator in ovarian cancer. Our data also provide an innovative interpretation for the apparent disconnection between low levels of zinc and up-regulation of ZIP4 in ovarian cancer tissues.
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