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The role of transcription factors in the pathogenesis of colorectal cancer

Colorectal cancer (CRC) is one of the most diagnosed malignancies and third most leading causes of death in the world. In the pathogenesis of CRC, a benign adenomatous polyp can develop into an invasive cancer through multiple routes of gene inactivation. One of the most common mutations found in CRC is a loss of function mutation of APC. Wild-type APC forms a destruction complex with Axin2 and GSK-3β to degrade β-catenin in the cytosol. If β-catenin is not degraded, it can be translocated into the nucleus, wherewith the help of LSF it binds to the DNA and initiates Wnt signaling. The Wnt pathway is responsible for the upregulation of pro-oncogenic genes. The components of this pathway have become a prime target for CRC drug therapies. In this study, we examined the effectiveness of a newly developed drug named FQI-234. FQI-234 is designed to target LSF and hinder its ability to modulate the binding of β-catenin to DNA. An animal model was developed and 20 nude mice were subcutaneously injected with HT-29 cells. Following approximately one week, 10 mice were randomly selected to be in the experimental group and given 15 administrations of FQI-234 at 5 mg/kg over three weeks. Volumes of the tumors from each mouse were calculated throughout the experiment and at its conclusion. These calculations revealed a slower growth rate and smaller volume in those tumors treated with FQI-234. Tumors were then harvested and divided. Half of the tumors halves were used for RT-PCR and the other halves were fixed in formalin, embedded in paraffin, and then stained for histological examination. IHC staining exhibited a downregulation in levels of β-catenin, LSF, Axin2, and Sox9. Suppression of cell proliferation and upregulation of cell apoptosis was also evident. RT PCR confirmed these results with a decrease in levels of Axin2, Sox9, and Cyclin D1 shown in the xenografts treated with FQI-234. Overall this study showed for the first time in an animal model the tumor-suppressive effects of the LSF targeted compound, FQI-234. / 2023-12-14T00:00:00Z

Identiferoai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/43541
Date14 December 2021
CreatorsLo, Dominic
ContributorsChitalia, Vipul, Lotfollahzadeh, Saran
Source SetsBoston University
Languageen_US
Detected LanguageEnglish
TypeThesis/Dissertation

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