Theses and Dissertations from UMD

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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM

More information is available at Theses and Dissertations at University of Maryland Libraries.

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2016 - 20202

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Author: search.filters.author.Lou, Zhiyuan

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    THE ROLE OF ESE-1 IN NON-SMALL CELL LUNG CANCER (NSCLC) CELLS
    (2020) Lou, Zhiyuan; Lee, Seong-Ho; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Lung cancer is the most life-threatening cancer in the world. The identification of the effective molecular target is essential for lung cancer prevention and therapy. Epithelial Specific ETS-1 (ESE-1) is a transcription factor associated with several types of cancer. However, the significance of ESE-1 in human non-small cell lung cancer (NSCLC) remains unclear. The objective of this dissertation was to investigate if ESE-1 expression influences the tumorigenic and metastatic activity of human non-small cell lung cancer (NSCLC) and to explore the mechanisms associated with tumorigenesis and epithelial mesenchymal transition (EMT). Overexpression of ESE-1 repressed the anchorage-independent growth of human NSCLC cells (H1299 and H1703) and led to an increase of G1 arrest and apoptosis, additionally, to repress invasion and migration. Xenograft study indicated that ESE-1 expression inhibited the formation and development of the tumor. In terms of mechanistic studies, overexpression of ESE-1 downregulates NF-κB transcriptional activity in both H1299 and H1703 cells. The downregulation might be associated with inhibition of NF-κB-p65 phosphorylation. ESE-1 is a downstream target of TGF-β-stimulated EMT. Downregulation of ESE-1 by TGF-β is dependent on Smad2/3, but not on Smad4 and other alternative pathways, including ERK, p38 MAPK, JNK, RAS, GSK3, PI3K, NF-ĸB, CDC42, PKC, and Rock signaling. We identified two putative Smad responsive elements (SRE) in the ESE-1 promoter. After cloning internal deletion and point mutated clones lacking distal and proximal SRE, which were localized at the distal and proximal regions of the ESE-1 promoter between -1500 to -713, the double mutation responsible for ESE-1 transcriptional downregulation with TGF-β induction. Moreover, EMT downstream target Snail reciprocally interacts with ESE-1. Our findings indicate that ESE-1 serves as a tumor repressor in ESE-1-null NSCLC cells, and we propose a potential use of ESE-1 as a target of lung cancer chemoprevention.
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    ANTICANCER MECHANISM OF TOLFENAMIC ACID IN COLORECTAL CANCER
    (2016) Lou, Zhiyuan; Lee, Seong-Ho; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States. Chemopreventive therapies could be effective way to treat CRC. Tolfenamic acid, one of the NSAIDs, shows anti-cancer activities in several types of cancer. Aberrant Wnt/β-catenin regulation pathway is a major mechanism of colon tumorigenesis. Here, we sought to better define the mechanism by which tolfenamic acid suppresses colorectal tumorigenesis focusing on regulation of β-catenin pathway. Treatment of tolfenamic acid led to a down-regulation of β-catenin expression in dose dependent manner in human colon cancer cell lines without changing mRNA. MG132 inhibited tolfenamic acid-induced downregulation of β-catenin and exogenously overexpression β-catenin was stabilized in the presence of tolfenamic acid. Tolfenamic acid induced an ubiquitin-mediated proteasomal degradation of β-catenin. In addition, tolfenamic acid treatment decreased transcriptional activity of β-catenin and expression of Smad2 and Smad3 while overexpression of Smad 2 inhibited tolfenamic acid-stimulated transcriptional activity of β-catenin. Moreover, tolfenamic acid decreased β-catenin target gene such as vascular endothelial growth factor (VEGF) and cyclin D1. In summary, tolfenamic acid is a promising therapeutic drug targeting Smad 2-mediated downregulation of β-catenin in CRC.