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Transcription Factor Dysfunction in Ovarian Cancer: The Role of ZIC2 and RUNX3
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- Author / Creator
- Chen, Huachen
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Ovarian cancer is the most lethal gynecological cancer, and epithelial ovarian cancer (EOC) accounts for about 90% of ovarian cancers. Despite advancements in medical technology, the overall survival rate of EOC has improved only slightly, with a 5-year survival rate of less than 50%. One cause is the development of chemoresistance in EOC after conventional chemotherapy, which may be due to the presence of cancer stem cells (CSCs). ZIC2 is a transcription factor that is expressed in embryonic stem cells but not in adult tissues except the brain and testis. Upregulation of ZIC2 is pro-tumorigenic in a variety of human cancers. However, limited studies have been conducted on ZIC2-mediated regulation of tumorigenic phenotypes and the related molecular mechanisms of ZIC2 in EOC. We hypothesized that ZIC2 promotes tumorigenic phenotypes in EOC. Herein, we reported that ZIC2 is expressed in a subpopulation of EOC samples and is associated with poor survival in patients with advanced EOC. ZIC2 promotes cell growth, single-cell survival, anchorage-independent growth, and CSC stemness, but it is cell-context dependent. Furthermore, we demonstrated potential underlying mechanisms for ZIC2-mediated regulation of tumorigenic phenotypes in EOC.We also investigated the role of the transcription factor RUNX3 in a rare subtype of ovarian cancer, granulosa cell tumor of the ovary (GCT). GCTs are classified as adult granulosa cell tumors (AGCT) and juvenile granulosa cell tumors (JGCT). Although most GCTs are diagnosed at early stages, patients with advanced GCTs have a poor prognosis and are prone to relapse. RUNX3 has been shown to play an important role in normal tissues and human cancers. RUNX3 plays a role in inhibiting or promoting tumor progression in various human cancers. In EOC, RUNX3 promotes cell proliferation, anchorage-independent growth, and chemoresistance. We hypothesized that RUNX3 promotes the tumorigenic phenotypes in GCT. We reported the expression of RUNX1, RUNX2, and RUNX3 in GCT, where RUNX3 showed low levels of variable expression in GCT samples but not in the normal human granulosa cell line SVOG or normal ovarian tissues. RUNX3 also promotes cell growth, anchorage-independent growth, cell motility, and tumor formation in the AGCT cell line KGN, while inhibition of RUNX3 in the JGCT cell line COV434 reduces cell growth. Moreover, RUNX3 upregulates the expression of cyclin D2 and reduces the expression of P27Kip1 in KGN cells. Collectively, this study suggests that ZIC2 and RUNX3 play a pro-tumorigenic role in ovarian cancer in a context-dependent manner and are potential therapeutic targets for ovarian cancer.
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- Subjects / Keywords
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- Graduation date
- Spring 2022
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.