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dc.contributor.authorChen, Xi
dc.date.accessioned2023-02-17T14:01:46Z
dc.date.available2023-02-17T14:01:46Z
dc.date.issued2022
dc.identifier.urihttp://hdl.handle.net/10713/20381
dc.descriptionUniversity of Maryland, Baltimore. Biochemistry. Ph.D. 2022.en_US
dc.description.abstractEpidermal squamous cell carcinoma is among the most common cancers in humans. It is typically treated by surgical resection and chemotherapy. However, 5 – 10% of resected cases relapse as aggressive cancer. We attribute the reason as the existence of epidermal cancer stem-like cells (ECS cells). Transglutaminase 2 (TG2) is a key ECS cell survival protein. However, how TG2 maintains the aggressive ECS cell cancer phenotype is not well understood. Thus, our goal is to identify TG2-stimulated downstream mediators that are important to maintain the ECS cell cancer phenotype. In the present studies, we show that inhibition of TG2 reduces MET tyrosine kinase receptor expression and activity, and that this is associated with attenuated cancer phenotype. Inhibition of TG2 or HGF/MET function reduces downstream MEK1/2-ERK1/2 activity, and this is associated with reduced cancer cell spheroid formation, invasion, migration, and reduced EMT and stem cell marker expression. HGF partially restores the aggressive cancer phenotype, confirming that MET signaling is downstream of TG2. MET knockdown reduces ERK1/2 signaling, doubles the time to initial tumor appearance and reduces overall tumor growth. In addition, we show that TG2 knockdown or inactivation results in a reduction in mTOR level and activity in ECS cells which are associated with reduced spheroid formation, invasion, migration, and reduced stem cell and EMT marker expression. mTOR knockdown or treatment with the mTOR inhibitor rapamycin phenocopies the reductions in cancer phenotype and stem cell and EMT marker expression. Moreover, forced expression of constitutively active mTOR in TG2 knockdown cells partially restores the aggressive cancer phenotype and stem cell and EMT marker levels, suggesting that mTOR is a necessary mediator of TG2 action. Together, the present studies suggest that TG2 maintains HGF/MET/ERK1/2 signaling and mTOR signaling to maintain the aggressive ECS cell cancer phenotype and drive aggressive tumor formation, and that TG2-dependent MET or mTOR signaling may be useful anti-cancer targets.en_US
dc.language.isoen_USen_US
dc.subject.meshProtein Glutamine gamma Glutamyltransferase 2en_US
dc.subject.meshCarcinoma, Squamous Cellen_US
dc.subject.meshPhenotypeen_US
dc.titleIdentifying transglutaminase 2 (TG2) downstream mediators that are required to maintain an aggressive epidermal squamous cell carcinoma cancer phenotypeen_US
dc.typedissertationen_US
dc.date.updated2023-02-10T17:06:46Z
dc.language.rfc3066en
dc.contributor.advisorEckert, Richard (Richard L.)
refterms.dateFOA2023-02-17T14:01:47Z


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