Abstract
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.
Highlights
Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer
the zinc transporter 4 (ZIP4) and other cancer stem cell (CSC) markers in EOC were overexpressed in human EOC tissues and in ID8-P1 vs. ID8-P0 cells
The TCGA and Oncomine data suggest that the ZIP4 gene is over-expressed in EOC [14]
Summary
Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. The Cancer Genome Atlas(TCGA)data have set the genetic landscape of EOC [1]. Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer. Data have set the genetic landscape of EOC [1]. We have developed a highly aggressive EOC cell line (ID8-P1) through in vivo passage of ID8-P0 cells in C57BL6 mice [2]. The tumor/ascites formation time is reduced from www.impactjournals.com/oncotarget. ~90 days for ID8-P0 cells to ~30 days in different ID8-P1 cell lines isolated from tumors in different organs or from ascites [2]. RNAseq data in two independent pairs of ID8-P0 and ID8-P1 cells were obtained. Zip is among the genes highly up-regulated in ID8-P1 vs ID8-P0 cells
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