Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health

First Advisor

Vasiliou, Vasilis

Abstract

Both liver and colon cancers comprise the heterogeneous complex array of disorders, ranking the most common malignancies worldwide [1-3]. In 2022, the estimated 41,260 new cases of liver cancers and 106,180 new cases of colon cancers diagnosed in the United States, with 30,520 and 52,580 estimated deaths of corresponding cancers [4, 5]. A combination of surgery, chemotherapy, and/or radiotherapy is currently used to treat these cancers, and the five-year survival rate remains low for most of them [1-5]. This high lethality makes liver and colon cancers a major public health issue [6-11]. Despite extensive efforts over decades to characterize the molecular pathogenesis of liver and colon cancers, the precise mechanisms of development and progression are still largely unknown [12, 13]. Epidemiological studies provide strong evidence of a link between liver and colon cancers and environmental factors, including high dietary fat intake, limited physical activity, and exposure to ionizing radiation or environmental carcinogens [3, 14, 15]. Among these key etiological factors, environmental carcinogens appear to have the most adverse impact on colon and liver carcinogenesis [14-16]. A group of known human carcinogens is categorized by the International Agency for Research on Cancer (IARC) either because they do not deactivate by enzymes or because they generate reactive moieties that cause cancer [17-19]. IARC also classifies compounds as suspected human carcinogens with possible carcinogenic effects [20]. Members of this group of carcinogens are often identified based on the emerging evidence of contamination accompanied by carcinogenicity, with limited evidence of mechanisms of carcinogenicity in experimental animals or populations [20]. For example, For example, several population studies found an emerging water contaminant, known as the 1,4-dioxane (DX), linked to liver adenomas and carcinoma in vitro and in vivo [21, 22], though the detailed mechanism by which DX may mediate liver injury remains unknown [23]. Carcinogens are metabolized, eliminated, and detoxified by xenobiotic processing enzymes found in mucosal surfaces of the body (lungs, the gastrointestinal tract, urogenital system, etc.) and the liver [24]. As "bridges" between the natural environment and the human body, these enzymes play a critical role in the conversion of normal cells into the precursor or premalignant lesions and ultimately cancer cells by (i) bioactivating dietary and environmental components to generate carcinogens, (ii) inducing chemo-resistance through altered enzyme expression, and (iii) metabolizing (sometimes activating) drugs used for cancer treatment [25-27]. Subject to their versatile functions, these enzymes are regarded as potential targets for anticancer therapy [27]. However, the understanding of the mechanisms of carcinogens is limited to selected enzymes in cell type- and tissue-specific contexts [28]. Therefore, further elaboration of xenobiotic metabolism may aid the risk stratification of vulnerable populations based on genetic and environmental factors to further contribute to the development of screening programs and tailored pharmacological treatments. A large diversity and abundance of cytochrome P450 (CYP) enzymes make them the most important enzymes for metabolizing xenobiotics [29, 30]. CYP enzymes are responsible for 70–80% of xenobiotic metabolism [28, 30]. Since Omura and Sato first named CYP enzymes in 1962, numerous CYP enzymes have been discovered [30, 31]. This group of enzymes plays important roles in phase I enzyme reactions, which involve detoxification and metabolic activation through oxidation, reduction, hydroxylation, etc. [30, 31]. By activating or inactivating carcinogens, CYP enzymes play a critical role in xenobiotic carcinogenesis [30]. In particular, cytochrome P450 2E1 (CYP2E1) accounts for 95% of xenobiotic oxidation and reduction and is actively involved in xenobiotic-induced hepatotoxicity and cancers (e.g., gastric and colorectal cancer) [32]. Studies of alcohol/chemical-mediated carcinogenesis have shown that CYP2E1 induction is an essential response to xenobiotic exposure [33]. CYP2E1-related oxidative stress and metabolic activation of potentially toxic substrates result in DNA adduct formation, ultimately leading to toxicity and pathogenesis [33-35]. As the number of new potential carcinogens grows, studies of the general applicability of CYP2E1-dependent mechanisms are increasingly important. Another group of xenobiotic metabolism enzymes that has attracted significant attention in cancer research is the aldehyde dehydrogenase (ALDH) superfamily [36]. This group of metabolic enzymes detoxify endogenous and exogenous aldehydes, which are involved in various functions associated with cell maintenance, differentiation, and proliferation [36]. The increased expression of ALDH enzymes is observed in various cancers and utilized as a marker of cancer cells and cancer stem cells (CSCs) [37, 38]. As the principal alcohol-metabolizing enzyme, a substantial body of evidence indicates that ALDHs contribute to the risk of alcoholic complications and to the proliferation and invasiveness of different GI cancers [39-41]. Most notably, ALDH1B1 is profoundly upregulated in colonic adenocarcinoma and has been identified as an immunobiological marker distinguishing colon cancer tissues from normal tissues for therapy [42, 43]. Our previous work suggests that ALDH1B1 is not only a biomarker for colon cancer prognosis but also promotes colon cancer tumorigenesis [42]. However, the precise mechanism of ALDH1B1 in colon carcinogenesis remains unknown. In this dissertation work, I used the stable RNAi gene knockdown cell lines and transgenic mice to explore new functions and mechanisms of xenobiotic metabolism in liver and colon carcinogenesis. First, I investigated the impact of exposure to an emerging suspected human carcinogen, dioxane (DX), on the general functions and mechanisms of xenobiotic enzymes. Specifically, I tested the hypothesis the essentiality of CYP2E1 for DX associated liver cytotoxicity and genotoxicity. Cyp2e1-null (Cyp2e1KO) male and female mice were treated with 5000 ppm DX in drinking water for 1 week and 3 months. Second, I hypothesized that in addition to their well-established functions, xenobiotic enzymes have specific roles in regulation or other unknown mechanisms during carcinogenesis. To test this hypothesis, I performed the comprehensive multi-omics analysis of the SW480 ALDH1BI knockdown (KD) and scramble (SC) cells to obtain new insights into the novel functions of ALDH1B1 in colon cancer.

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