Fan, QipengZhang, WenEmerson, Robert E.Xu, Yan2022-04-202022-04-202020-12-09Fan Q, Zhang W, Emerson RE, Xu Y. ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer. Cancers (Basel). 2020 Dec 9;12(12):3692. doi: 10.3390/cancers12123692. PMID: 33316986; PMCID: PMC7764492.https://hdl.handle.net/1805/28621High-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.en-USAttribution 4.0 United StatesALDHCancer stem cell (CSC)High-grade serous ovarian cancer (HGSOC)NOTCH3ZIP4Article