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Identification and Analysis of Compounds To Improve CTNNB1-mutated Hepatocellular Carcinoma (HCC) in Transgenic Zebrafish

Year: 2023

Presenter Name: Audrey Su

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a 5-year survival rate of <20%, and it was the sixth leading cause of cancer mortality in 2020. One of the most commonly mutated genes in HCC is β-catenin (CTNNB1), accounting for ~20-40% of patients with HCC and leading to constitutively active Wnt signaling. Due to the necessity of Wnt signaling in healthy liver tissue, there are few precision medicine-based treatments for patients with either CTNNB1-mutated HCC or HCC as a whole. Instead of targeting specific mutated protein(s), this research focuses on analyzing dysregulated pathways downstream that are susceptible to treatment. Our aim is to characterize the effects of mutated CTNNB1 on lipid metabolism and tumorigenesis. To understand the role of lipid metabolism in HCC, we screened 194 metabolic/protease-related compounds using our lab's transgenic CTNNB1 zebrafish model of HCC. Wild-type and transgenic larvae were exposed to either DMSO control or experimental compound from 3 to 6 days post fertilization (dpf), and liver size was recorded at 6 dpf. Compounds that decreased liver size in transgenic zebrafish were considered positive hits. We confirmation-tested 10 compounds with additional doses and greater sample sizes. Our results showed that FAAH-IN2 and pitavastatin decreased larval liver size in transgenic zebrafish, while GSK1940029 increased liver size. To further characterize these compounds' effects, we used oil red-o staining to analyze changes in lipid storage. Our work successfully identified key compounds that significantly affect larval liver size in transgenic zebrafish. These findings could lead to better treatments for both CTNNB1-mutated HCC and HCC as a whole. Future work includes studying differences in hepatocyte proliferation and analyzing alterations in immune cell migration in zebrafish treated with FAAH-IN2, pitavastatin, and GSK1940029, as well as continued confirmation testing in remaining compounds.
University / Institution: University of Utah
Type: Oral
Format: In Person
SESSION C (1:45-3:15PM)
Area of Research: Health & Medicine
Faculty Mentor: Kimberley Evason
Location: Sill Center Conference Room (2:45pm)