• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Identifying transglutaminase 2 (TG2) downstream mediators that are required to maintain an aggressive epidermal squamous cell carcinoma cancer phenotype

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Chen_umaryland_0373D_11405.pdf
    Embargo:
    2023-07-01
    Size:
    6.655Mb
    Format:
    PDF
    Download
    Author
    Chen, Xi cc
    Advisor
    Eckert, Richard (Richard L.)
    Date
    2022
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Epidermal 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.
    Description
    University of Maryland, Baltimore. Biochemistry. Ph.D. 2022.
    Keyword
    Protein Glutamine gamma Glutamyltransferase 2
    Carcinoma, Squamous Cell
    Phenotype
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/20381
    Collections
    Theses and Dissertations School of Medicine
    Theses and Dissertations All Schools

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.