p53 Regulates Stemness in Mucoepidermoid Carcinoma
dc.contributor.author | Rodriguez Ramirez, Christie | |
dc.date.accessioned | 2020-10-04T23:23:04Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2020-10-04T23:23:04Z | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/162925 | |
dc.description.abstract | Salivary gland carcinomas are rare and heterogenous malignancies that present diagnostic and treatment challenges for clinicians. Amongst them, mucoepidermoid carcinoma (MEC) is the most common salivary gland cancer. Little is known about the pathobiology of MEC, partly due to limited preclinical research models. Our group and others have shown that cancer stem cells (CSC), ALDHhighCD44high cells, drive MEC tumorigenesis. We have found that treatment of human MEC cell lines (UM-HMC-1, UM-HMC-3A, UM-HMC-3B) with sub-lethal doses of MI-773, an MDM2 inhibitor that results in accumulation of p53 and activation of downstream signaling, significantly decreases the CSC fraction both in vitro and in xenograft tumors. Furthermore, upon p53 activation there is a decrease in Bmi-1 protein levels. Bmi-1 has been widely studied as a marker of stem cell and CSC self-renewal. We hypothesized that the p53 pathway regulates MEC CSC maintenance. In this thesis we aim to: 1) determine the role of p53 in MEC CSC fate and 2) investigate the therapeutic potential of MDM2 inhibitors in murine models of MEC. We found that while activation of p53 signaling does not cause apoptosis of MEC CSCs, it changes their cell cycle profile through p21. Furthermore, p53 activation causes a decrease in the sphere forming ability and self-renewal of MEC CSCs and in their Bmi-1 protein levels, independent of p21 signaling. Additionally, we found an induction of pan-cytokeratin expression, indicating differentiation of the CSCs. In contrast, shRNA downregulation of p53 resulted in increased Bmi-1 protein levels, enhanced CSC self-renewal, and an expansion of the stem cell pool in vivo. While no changes in Bmi-1 mRNA levels were detected after treatment with MDM2 inhibitors, we found a decrease in Bmi-1 protein stability. Importantly, we found that therapeutic activation of p53 using MI-773 prevented tumor recurrence in mice. Further characterization of the regulation of Bmi-1 by p53 still needs to be evaluated. These results indicate p53 signaling regulates the cell cycle and self-renewal of MEC CSC through p21 and Bmi-1 signaling axes. This body of work enhances our understanding of the role of p53 in MEC CSC biology and gives insight into the potential therapeutic benefits of MDM2 inhibitors or other p53-activating therapies for MEC. | |
dc.language.iso | en_US | |
dc.subject | p53 regulates stemness in mucoepidermoid carcinoma | |
dc.subject | p53 regulates cancer stem cell fate | |
dc.subject | salivary gland cancer stem cells | |
dc.title | p53 Regulates Stemness in Mucoepidermoid Carcinoma | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Cancer Biology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Nor, Jacques Eduardo | |
dc.contributor.committeemember | Beer, David G | |
dc.contributor.committeemember | Ljungman, Mats E D | |
dc.contributor.committeemember | Polverini, Peter J | |
dc.contributor.committeemember | Wicha, Max S | |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/162925/1/chrisrr_1.pdf | en_US |
dc.identifier.orcid | 0000-0002-3413-4926 | |
dc.identifier.name-orcid | Rodriguez-Ramirez, Christie; 0000-0002-3413-4926 | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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