Date of Award

2023

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Biological Sciences

First Advisor

Dr. Ivana Vancurova

Second Advisor

Dr. Ales Vancura

Third Advisor

Dr. Matteo Ruggiu

Abstract

Interferon gamma (IFNγ) is a pleiotropic cytokine that can have, depending on the cellular and molecular context, both anti-tumor and pro-tumorigenic functions. IFNγ expression can be induced in cancer cells in response to radiation therapy or immune checkpoint blockade used in cancer treatment. We have previously shown that IFNγ induces expression of the Bcl3 proto-oncogene in ovarian cancer (OC) cells, resulting in their increased proliferation and migration, but the mechanisms are unknown. Here, I demonstrate that the IFNγ-induced Bcl3 expression is dependent on JAK1 and STAT1 signaling, and on p65 NFkB. Furthermore, my data show that the IFNγ-induced Bcl3 expression is associated with an increased occupancy of Ser-727 phosphorylated STAT1 and acetylated histone H3 at human Bcl3 promoter. In addition, my results demonstrate that IFNγ induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) that is dependent on Bcl3 in OC cells and that IL-8 neutralization significantly decreases invasion of IFNγ-stimulated OC cells grown in 3D spheroids. Together, these findings identify Bcl3 as a novel target of the IFNγ/JAK1/STAT1 signaling and suggest that targeting the JAK1/STAT1 pathway may suppress the IFNγ-induced Bcl3 and IL-8 expression in ovarian cancer.

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