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Transcription factor ZIC2 regulates the tumorigenic phenotypes associated with both bulk and cancer stem cells in epithelial ovarian cancer

Oncogene (2024)Cite this article

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Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in North America. Current therapeutic regimens are ineffective against advanced EOC. A better understanding of the molecular mechanisms that regulate the biology of EOC will be a critical step toward developing more efficacious therapies against EOC. Herein, we demonstrate that elevated expression of transcription factor ZIC2 was associated with lower survival of EOC patients. Knockout of endogenous ZIC2 in EOC cells attenuated the tumorigenic phenotypes associated with both bulk and cancer stem cells in vitro and in vivo, indicating a pro-tumorigenic role of ZIC2 in EOC. On the other hand, however, overexpression of ZIC2 in EOC cells that do not express endogenous ZIC2 promoted cell migration and sphere formation, but inhibited cell growth and colony formation in vitro and tumor growth in vivo, indicating that the role for ZIC2 in EOC is context dependent. Our transcriptomic analysis showed that ZIC2-regulated genes were involved in multiple biological processes and signaling pathways associated with tumor progression. In conclusion, our findings reveal a context-dependent role for ZIC2 in regulating tumorigenic phenotypes in EOC, providing evidence that ZIC2 can be a potential therapeutic target for EOCs that express a high level of ZIC2.

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Fig. 1: Expression of ZIC2 in EOC.
Fig. 2: Knockout of ZIC2 mitigates tumorigenic phenotypes in EOC cells.
Fig. 3: ZIC2 KO reduces the cancer stem cell phenotype in EOC cells.
Fig. 4: ZIC2 overexpression exhibits variable effects on the characteristics of EOC cells.
Fig. 5: Overexpression of ZIC2 augments the cancer stem cell-like phenotype in EOC cells.
Fig. 6: ZIC2 regulates transcriptome in EOC cells.
Fig. 7: Validation of the differentially expressed genes in SKOV3 and OVCAR3 cells.
Fig. 8: A potential model for ZIC2 functions in EOC.

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Data availability

RNA-sequencing data have been deposited in NCBI’s Gene Expression Omnibus (GEO) database and are accessible through GEO Series accession number GSE227395.

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Acknowledgements

This research has been funded by the Alberta Women’s Health Foundation through the Women and Children’s Health Research Institute (WCHRI) to YXF; funding from the Alberta Cancer Foundation and WCHRI to L-MP. L-MP is the Sawin-Baldwin Chair in Ovarian Cancer & Dr. Anthony Noujaim Legacy Oncology Chair and the Alberta Innovates Health Solutions Translational Chair in Cancer. HC was supported by graduate studentships from the Li Ka Shing Foundation and Yau Family Foundation. LJL was supported by the Alberta Innovates MD-PhD Studentship, CIHR Doctoral Research Award and Alberta Cancer Foundation Graduate Studentship. We thank Dr. Xuejun Sun at the Cell Imaging and Flow Cytometry Facility of the Oncology Department at the University of Alberta at the Cross Cancer Institute for cell imaging and sorting and Dr. Aja Rieger in the flow cytometry facility of the University of Alberta.

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Authors and Affiliations

  1. Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Huachen Chen, Laura Jiyoung Lee, Krista M. Vincent, Zhihua Xu, Jiahui Liu, Guihua Zhang, Zorica Nakevska, Lynne-Marie Postovit & YangXin Fu

  2. Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    DuPreez Smith, Lynne-Marie Postovit & YangXin Fu

  3. Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Cheng-Han Lee

  4. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Lynne-Marie Postovit

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Contributions

H. Chen: Formal analysis, investigation, methodology, validation, writing-original draft. L.J. Lee: Formal analysis and methodology. K.M. Vincent: Formal analysis. Z. Xu: Investigation. J. Liu: Investigation. G. Zhang: Investigation. L.M. Z Nakevska: Investigation. D. Smith: Investigation. C.H. Lee: Formal analysis, supervision, writing review and editing. Postovit: Conceptualization, funding acquisition, project administration, supervision, writing-review and editing. Y. Fu: Conceptualization, funding acquisition, project administration, supervision, writing-review and editing.

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Correspondence to Lynne-Marie Postovit or YangXin Fu.

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Chen, H., Lee, L.J., Vincent, K.M. et al. Transcription factor ZIC2 regulates the tumorigenic phenotypes associated with both bulk and cancer stem cells in epithelial ovarian cancer. Oncogene (2024). https://doi.org/10.1038/s41388-024-03026-z

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