The novel ZIP4 regulation and its role in ovarian cancer

Qipeng Fan; Qingchun Cai; Pengfei Li; Wenyan Wang; Jing Wang; Emily Gerry; Tian Li Wang; Ie Ming Shih; Kenneth P. Nephew; Yan Xu

doi:10.18632/oncotarget.21435

The novel ZIP4 regulation and its role in ovarian cancer

Qipeng Fan, Qingchun Cai, Pengfei Li, Wenyan Wang, Jing Wang, Emily Gerry, Tian Li Wang, Ie Ming Shih, Kenneth P. Nephew, Yan Xu

School of Medicine

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 highgrade 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.

Original language	English (US)
Pages (from-to)	90090-90107
Number of pages	18
Journal	Oncotarget
Volume	8
Issue number	52
DOIs	https://doi.org/10.18632/oncotarget.21435
State	Published - 2017

Keywords

Cancer stem cells (CSC)
LPA
Ovarian cancer
ZIP4

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.21435

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title = "The novel ZIP4 regulation and its role in ovarian cancer",

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 highgrade 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.",

keywords = "Cancer stem cells (CSC), LPA, Ovarian cancer, ZIP4",

author = "Qipeng Fan and Qingchun Cai and Pengfei Li and Wenyan Wang and Jing Wang and Emily Gerry and Wang, {Tian Li} and Shih, {Ie Ming} and Nephew, {Kenneth P.} and Yan Xu",

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AU - Fan, Qipeng

AU - Cai, Qingchun

AU - Li, Pengfei

AU - Wang, Wenyan

AU - Wang, Jing

AU - Gerry, Emily

AU - Wang, Tian Li

AU - Shih, Ie Ming

AU - Nephew, Kenneth P.

AU - Xu, Yan

N1 - Publisher Copyright: © Fan et al.

PY - 2017

Y1 - 2017

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The novel ZIP4 regulation and its role in ovarian cancer

Abstract

Keywords

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