Next Article in Journal
Role of Natural Killer Cells in Uveal Melanoma
Next Article in Special Issue
Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia
Previous Article in Journal
The Diagnostic and Therapeutic Role of Leptin and Its Receptor ObR in Glioblastoma Multiforme
Previous Article in Special Issue
Angiogenesis-Related Gene Expression Signatures Predicting Prognosis in Gastric Cancer Patients
Article

ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

1
Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA
2
Pharmaceutical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti Nanlu, Beijing 100020, China
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3692; https://doi.org/10.3390/cancers12123692
Received: 10 November 2020 / Revised: 3 December 2020 / Accepted: 7 December 2020 / Published: 9 December 2020
(This article belongs to the Special Issue Novel Biomarkers and Molecular Targets in Cancer)
Ovarian cancer is the most deadly gynecologic cancer. The treatment options for ovarian cancer, and for the recurrent cancer in particular, are limited. One of the major obstacles is the presence of drug-resistant cancer stem cells. The aim of this study is to identify and characterize a new cancer stem marker, namely ZIP4. ZIP4 is a transporter for human essential element zinc. Our results have shown that ZIP4 is not only a novel and potent stem cell marker, but also a target for developing innovative treatment for ovarian cancer. In addition, ZIP4 is interacting with another oncogene, NOTCH3. Both ZIP4 and NOTCH3 play important roles in tumor development in ovarian cancer. This interaction may represent a useful target for ovarian cancer treatment.
High-grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is functionally involved in cancer stem cell (CSC)-related cellular activities in HGSOC. Here, we identified ZIP4 as a novel CSC marker in HGSOC. Fluorescence-activated cell sorter (FACS)-sorted ZIP4+, but not ZIP4 cells, formed spheroids and displayed self-renewing and differentiation abilities. Over-expression of ZIP4 conferred drug resistance properties in vitro. ZIP4+, but not ZIP4 cells, formed tumors/ascites in vivo. We conducted limiting dilution experiments and showed that 100–200 ZIP4+ cells from both PE04 and PEA2 cells formed larger tumors than those from 100–200 ALDH+ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Genetic compensation studies showed that NOTCH3, but not NOTCH1, was a critical downstream mediator of ZIP4. Furthermore, NOTCH3, but not NOTCH1, physically bound to ZIP4. Collectively, our data suggest that ZIP4 is a novel CSC marker and the new ZIP4-NOTCH3 axis represents important therapeutic targets in HGSOC. View Full-Text
Keywords: ALDH; cancer stem cell (CSC); high-grade serous ovarian cancer (HGSOC); NOTCH3; ZIP4 ALDH; cancer stem cell (CSC); high-grade serous ovarian cancer (HGSOC); NOTCH3; ZIP4
Show Figures

Figure 1

MDPI and ACS Style

Fan, Q.; Zhang, W.; Emerson, R.E.; Xu, Y. ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer. Cancers 2020, 12, 3692. https://doi.org/10.3390/cancers12123692

AMA Style

Fan Q, Zhang W, Emerson RE, Xu Y. ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer. Cancers. 2020; 12(12):3692. https://doi.org/10.3390/cancers12123692

Chicago/Turabian Style

Fan, Qipeng; Zhang, Wen; Emerson, Robert E.; Xu, Yan. 2020. "ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer" Cancers 12, no. 12: 3692. https://doi.org/10.3390/cancers12123692

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop