Author ORCID Identifier

https://orcid.org/0000-0002-4266-0125

Date Available

5-9-2024

Year of Publication

2023

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Toxicology and Cancer Biology

Advisor

Dr. Qiou Wei

Abstract

Reactive oxygen species (ROS) are oxygen-containing free radicals and/or molecules that are more reactive than O2. ROS such as hydroxyl radical (•OH) and hydrogen peroxide (H2O2) are produced naturally in the body as a result of reactions such as aerobic respiration and oxidative protein folding. ROS undergo reduction-oxidation (redox) reactions and mediate cell signaling. Accumulation of excessive ROS can damage DNA, RNA, protein and lipids. Antioxidants are enzymes and small molecules that react with ROS to modulate redox signaling and to prevent and repair oxidative damage. Examples of antioxidants include glutathione, thioredoxin, superoxide dismutase, catalase, vitamin C and peroxiredoxin (Prx).

In mammals, there are six Prxs that reduce hydrogen peroxide, alkyl hydroperoxide and peroxynitrite to maintain redox balance and protect against oxidative stress. Different Prxs have similar functions but different subcellular distribution. Peroxiredoxin IV (Prx4) scavenges ROS and participates in oxidative protein folding in the endoplasmic reticulum. We hypothesized that Prx4 plays an oncogenic role in colorectal cancer. To understand the significance of the Prx4 in colorectal cancer formation, wildtype and Prx4-/- mice of FVB/N background were subjected to a standard protocol of colorectal carcinogenesis induced by sequential exposure to Azoxymethane and Dextran sulfate sodium (AOM/DSS). Compared with wildtype littermates, Prx4-/- mice had significantly fewer and smaller tumors. Histopathological analysis revealed that loss of Prx4 leads to increased cell death through lipid peroxidation and lower infiltration of inflammatory cells in the knockout tumors compared to wildtype. We also examined the role of Prx4 in the progression of colorectal cancer. Loss of Prx4 reduced migration and invasion of colon cancer cell lines in vitro. Additionally, orthotopic implantation of HCT116 cells into immunodeficient NSG mice resulted in significantly lower metastasis after Prx4 knockdown. Mechanistic studies showed the involvement of tumor suppressor DKK1 in reducing migration and invasion in Prx4 knockdown cells. Thus, Prx4 plays a pro-tumorigenic role in colorectal cancer initiation and progression. This dissertation identifies Prx4 as a promising therapeutic target for prevention and treatment of colorectal cancer and highlights the need for further research to bridge the gap to clinical application.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2023.221

Funding Information

This study was supported by funding from: The National Institutes of Health (National Cancer Institute R01CA222596, National Institute of Environmental Health Sciences T32ES07266), Department of Defense (W81XWH-16-1-0203), American Cancer Society (RSG-16-213-01-TBE), and the Kentucky Lung Cancer Research Program (KLCRP2016).

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