ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Differentiation in ZIP4 Expression and Isolation of ZIP4+ and ZIP4− Cells
2.2. Isolation of ZIP4+ and ZIP4− Cells
2.3. Differentiation and Renewal of ZIP4, and Drug Resistance Conferred by ZIP4
2.4. ZIP4 Represents a Highly Potent and Selective Marker for Tumor Formation In Vivo in HGSOC
2.5. NOTCH3 Was an Important Down-Stream Mediator for ZIP4’s Activity
2.6. ZIP4 Physically Interacted with NOTCH3
2.7. NOTCH3-KO Significantly Reduced Tumorigenesis In Vivo
3. Discussion
4. Materials and Methods
4.1. Reagents, Cell Lines, and Culture
4.2. The Patient-Derived Xenograft (PDX) Model and Human HGSOC Tissues
4.3. Western Blot Analysis
4.4. mRNA Expression Analyses Using Quantitative-PCR (Q-PCR)
4.5. Assessments of Spheroid Renewal and Differentiation
4.6. Coimmunoprecipitation (Co-IP)
4.7. Spheroids and Colony Formation Assay
4.8. Cytotoxicity Assay
4.9. Fluorescence-Activated Cell Sorting (FACS) Analysis and the ZIP4+ Cell Self-Renewal Assay
4.10. Xenograft Mouse Model
4.11. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cell Type | Injection Site | Cell No. | Mice No. | Survival Days | Ascites Vol. (mL) | Tumor No. | Tumor Sites |
PE04 ZIP4+ | I.P. | 10K | 7/7 | 47 ± 10 | 26.90 ± 14.55 | 249 ± 111 | D, F, L, M, Om, Ov, P, SI, PW |
PE04 ZIP4− | I.P. | 10K | 0/5 | 267 ± 30 | 0.00 | 0 | NONE |
PE04 ALDH+ | I.P. | 10K | 5/5 | 91 ± 13 | 14.00 ± 2.35 | 95 ± 44 | D, F, L, M, Ov, PW |
PE04 ALDH- | I.P. | 10K | 1/4 | 217 | 1.50 | 13 | D, W |
PEA2 ZIP4+ | I.P. | 10K | 5/5 | 102 ± 11 | 1.00 ± 0.60 | 17 ± 4 | Ov, M, P, SI, PW, L |
PEA2 ZIP4− | I.P. | 10K | 1/3 | 238 | 1.00 | 12 | PW, M |
Cell Type | Injection Site | Cell No. | Mice No. | Survival Days | Tumor Size (cm3) | Tumor No. | Tumor Sites |
PE04 ZIP4+ | S.C. | 100 | 3/4 | 110 ± 5 | 0.17 ± 0.16 | 1 | Front Left |
PE04 ZIP4+ | S.C. | 200 | 4/4 | 110 ± 5 | 2.24 ± 1.13 | 1 | Rear Left |
PE04 ALDH+ | S.C. | 100 | 2/3 | 110 ± 5 | 0.04 ± 0.06 | 1 | Front Right |
PE04 ALDH+ | S.C. | 200 | 3/3 | 110 ± 5 | 1.41 ± 0.76 | 1 | Rear Right |
PEA2 ZIP4+ | S.C. | 100 | 3/3 | 81 ± 21 | 2.30 ± 3.75 | 1 | Front Left |
PEA2 ZIP4+ | S.C. | 200 | 3/3 | 81 ± 21 | 5.85 ± 5.20 | 1 | Rear Left |
PEA2 ALDH+ | S.C. | 100 | 3/3 | 81 ± 21 | 0.02 ± 0.02 | 1 | Front Right |
PEA2 ALDH+ | S.C. | 200 | 3/3 | 81 ± 21 | 3.14 ± 5.12 | 1 | Rear Right |
Cell Type | Injection Site | Cell No. | Mice No. | Survival Days | Ascites Vol. (mL) | Tumor No. | Tumor Sites |
PE04 | I.P. | 5 × 106 | 5/5 | 42 ± 4 | 12.10 ± 3.25 | 137 ± 27 | D, M, Om, Ov, P, SI, PW |
PE04-NOTCH3-KO | I.P. | 5 × 106 | 6/6 | 161 ± 21 | 4.72 ± 1.53 | 36 ± 18 | D, M, Ov, PW |
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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
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 StyleFan, Qipeng, Wen Zhang, Robert E. Emerson, and Yan Xu. 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