Phosphoglucomutase 5 and hepatocellular carcinoma
Phosphoglucomutase 5 and hepatocellular carcinoma
| dc.contributor.advisor | Hoffmann, Peter R. | |
| dc.contributor.author | Martinez Rodriguez, Verena | |
| dc.contributor.department | Cell and Molecular Biology | |
| dc.date.accessioned | 2024-07-02T23:41:48Z | |
| dc.date.available | 2024-07-02T23:41:48Z | |
| dc.date.issued | 2024 | |
| dc.description.degree | Ph.D. | |
| dc.identifier.uri | https://hdl.handle.net/10125/108341 | |
| dc.subject | Cellular biology | |
| dc.subject | Biology | |
| dc.subject | Oncology | |
| dc.subject | biomarker | |
| dc.subject | hepatocellular carcinoma | |
| dc.subject | liver cancer | |
| dc.subject | PGM5 | |
| dc.title | Phosphoglucomutase 5 and hepatocellular carcinoma | |
| dc.type | Thesis | |
| dcterms.abstract | Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and accounts for the 5th most common cancer and the 3rd leading cause of cancer mortalities worldwide. HCC occurs most commonly in patients with underlying liver diseases such as cirrhosis caused by hepatitis B and C virus infections. Since patients with early-stage HCC do not present overt symptoms, this disease is often detected in very late stages. Curable treatment options are currently very limited and include surgery and liver transplantation, which is why it is of utmost importance to find suitable biomarkers for early detection. Phosphoglucomutase 5 (PGM5) belongs to the α-D-phosphohexomutase (PHM) family comprised of five members in humans and mice. Members of this family play roles in catalyzing essential metabolic reactions with PGM1 representing the most widely expressed and fully characterized in terms of structure and function. In contrast to the other family members, PGM5 is predominantly expressed in muscle tissues and localizes to the adherens junctions of smooth muscle cells (SMCs). Also, in contrast to the other PHM proteins that exhibit enzyme activity, data suggest that PGM5 may play a structural function within cells. This is supported by studies finding interactions between PGM5 and cytoskeletal proteins in a manner that enhances cell-cell adhesion and contractility. For reasons that have not been determined, decreased levels of PGM5 mRNA have been shown to be a common characteristic in various cancers, including HCC. However, little is known regarding the role that PGM5 or its decreased levels play in tumor development and progression. This thesis dissertation presents the results of our investigation of the role that PGM5 may play in HCC progression with the following specific objectives: (i), determine whether PGM5 protein levels change in HCC in both human and mice, (ii) evaluate whether the localization of PGM5 is altered during HCC progression in the liver, and (iii) determine the in vivo effects of PGM5 overexpression and KO on HCC progression using mouse models. The data presented herein show that, in human patient biopsies of HCC and other types of cancer, PGM5 protein levels are decreased. By using a mouse model of HCC, we show that PGM5 protein levels decrease over time as the tumor progresses. In the healthy liver, PGM5 is located in the smooth muscle cells surrounding arteries and veins of healthy blood vessels, most notably at the portal triads of the classic hepatic lobule. When HCC forms and progresses, this organized structure completely changes, causing a decrease in PGM5 protein levels. At late-stage HCC, abnormal masses enriched in PGM5 form. Interestingly, these structures are not characterized by smooth muscle surrounding blood vessels and instead are clusters of bile ducts. Our findings revealed that low PGM5 protein levels decreased with HCC progression and tissue localization was altered from vascular smooth muscle in healthy livers to bile duct enriched clusters found in larger tumor mass. Overexpressing PGM5 in a transgenic mouse model was found to coincide with decreased tumor progression in female mice, but issues were found in this experimental model that limited any conclusive interpretation regarding the direct effects of increasing PGM5 on HCC outcome. | |
| dcterms.extent | 148 pages | |
| dcterms.language | en | |
| dcterms.publisher | University of Hawai'i at Manoa | |
| dcterms.rights | All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner. | |
| dcterms.type | Text | |
| local.identifier.alturi | http://dissertations.umi.com/hawii:12155 |
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