Date of Award

January 2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Advisor

Donald Sens

Abstract

Urothelial carcinoma (UC) is a prevalent and aggressive malignancy arising in urothelial cells, with arsenic exposure recognized as a significant environmental risk factor. It is categorized into two primary subtypes based on the extent of cancer progression beyond the bladder’s muscle wall: non-muscle-invasive urothelial carcinoma (NMIUC) and muscle-invasive urothelial carcinoma (MIUC). While NMIUC is associated with a relatively favorable prognosis, progression to MIUC is more aggressive and leads to significantly worse outcomes, including poor treatment response and increased metastasis. Squamous differentiation (SD) in UC is an emerging hallmark of aggressive UC, with patients often having poor prognoses and developing chemoresistance, particularly in the MIUC subtype. SD is marked by the expression of basal keratins, such as KRT6. Although KRT6 is recognized as a biomarker for SD, its functional role in driving disease progression in UC remains inadequately understood. Furthermore, SOX2, a transcription factor implicated in cancer stem cell properties and resistance to chemotherapy, has been associated with recurrence, metastasis, and poor prognosis in UC. This study will investigate SOX2’s role in regulating SD and the therapeutic potential of inhibiting SOX2 expression. Despite progress, the interplay between SOX2, cancer stem cell properties, and chemoresistance in UC progression remains inadequately understood. We hypothesize that the knockdown of KRT6 and SOX2 in UC cells will disrupt key signaling pathways involved in tumor growth, differentiation, and chemoresistance. Targeting either KRT6, the end marker of SD, and SOX2, a potential upstream regulator, may enhance the therapeutic response and reduce tumor growth in UC. This study is the first to investigate the functional repercussions of KRT6 and SOX2 knockdown in UC with SD models, marking a substantial milestone and paving the way for a better understanding of their pathological role in UC. The outcomes of this study have the potential to guide future therapeutic interventions targeting KRT6 and SOX2 to enhance our comprehension of their significance in UC research. The outcomes of this study may lead to the development of novel treatment strategies that target KRT6 and SOX2, potentially improving patient outcomes for those with aggressive and chemoresistant forms of UC.

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