{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T03:48:35Z","timestamp":1780458515425,"version":"3.54.1"},"reference-count":79,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T00:00:00Z","timestamp":1607472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mary Fendrich-Hulman Charitable Trust Fund","award":["YX"],"award-info":[{"award-number":["YX"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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\u2212 cells, formed spheroids and displayed self-renewing and differentiation abilities. Over-expression of ZIP4 conferred drug resistance properties in vitro. ZIP4+, but not ZIP4\u2212 cells, formed tumors\/ascites in vivo. We conducted limiting dilution experiments and showed that 100\u2013200 ZIP4+ cells from both PE04 and PEA2 cells formed larger tumors than those from 100\u2013200 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.<\/jats:p>","DOI":"10.3390\/cancers12123692","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T20:18:22Z","timestamp":1607631502000},"page":"3692","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer"],"prefix":"10.3390","volume":"12","author":[{"given":"Qipeng","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA"},{"name":"Pharmaceutical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongti Nanlu, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Emerson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8445-7996","authenticated-orcid":false,"given":"Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut St. R2-E380, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rojas, V., Hirshfield, K.M., Ganesan, S., and Rodriguez-R, L. (2016). Molecular characterization of epithelial ovarian cancer: Implications for diagnosis and treatment. Int. J. Mol. 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