Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Alvaro N.A. Monteiro, Ph.D.

Committee Member

Shelley Tworoger, Ph.D.

Committee Member

Florian Karreth, Ph.D.

Committee Member

Jamie Teer, Ph.D.

Committee Member

Simon Gayther, Ph.D.

Keywords

HOXA5, Norepinephrine, HGSOC, Stress

Abstract

Ovarian cancer remains one of the most lethal gynecological cancer and ranks eighth in cancer-related mortality among women. The high mortality rate can be attributed to majority of the cases being diagnosed at advanced stages of the disease when the survival rate and overall prognosis are poor. There is lack of effective screening modalities to detect ovarian cancer at early stages. Hence, a better understanding of the molecular mechanisms leading to ovarian cancer initiation is required.

Epidemiological studies have reported that conditions which cause chronic behavioral stress are associated with a higher risk of developing ovarian cancer. The activation of the sympathetic nervous system during stress leads to rapid release of catecholamines. In the ovary, norepinephrine (NE) has been identified as the most abundant catecholamine. Several studies have shown that high level of NE is associated with poor prognosis and can contribute to tumor progression by promoting survival, growth, migration and invasion of ovarian cancer cells. Although the effect of NE stimulation in ovarian cancer progression is well studied, its role in initiation of ovarian cancer remains mostly unknown.

The purpose of this study is to explore the extent to which NE can influence ovarian cancer initiation. Therefore, we used normal cell lines that are presumed to be the cells of origin for ovarian cancer - fallopian tube surface epithelial cells and ovarian surface epithelial cells. We conducted a short-term/acute NE stimulation experiment in which cells were treated with NE for 15 mins, 1 h and 4 h. In addition, we also conducted a long-term/chronic NE stimulation experiment in which the cells were continuously exposed to NE for 137 days. In this study, we provide evidence that acute vs chronic NE stimulation have distinct transcriptional profiles. Additionally, we identify transcription factor HoxA5 to be induced by short-term NE treatment and provide evidence for the attenuation of HoxA5 induction in long-term treated NE cells. In summary, this project explores the role of NE in ovarian cancer initiation and highlights the difference between acute vs chronic NE stimulation in the precursor cells of ovarian cancer.

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