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Activation of Glucocorticoid Receptor Signaling Inhibits KSHV-Induced Inflammation and Tumorigenesis

Chen, Luping (2024) Activation of Glucocorticoid Receptor Signaling Inhibits KSHV-Induced Inflammation and Tumorigenesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Hyperinflammation is the hallmark of Kaposi’s sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone, which functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone treatment induced IκBα expression resulting in inhibition of the NF-κB pathway and subsequent IL-1α expression. These results reveal an important role of the IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, Lupingluc36@pitt.eduluc360000-0001-7017-9972
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGuo, Haitaoguoh4@upmc.edu
Thesis AdvisorGao, Shou-Jianggaos8@upmc.edushg88
Committee MemberDeFranco, Donalddod1@pitt.edudod1
Committee MemberRich, Jeremyrichjn@upmc.edu
Committee MemberThomas, Garythomasg@pitt.edu
Date: 16 September 2024
Date Type: Publication
Defense Date: 12 January 2024
Approval Date: 16 September 2024
Submission Date: 2 April 2024
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 134
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Integrative Systems Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Kaposi’s sarcoma (KS), Kaposi’s sarcoma-associated herpesvirus (KSHV), inflammation, dexamethasone, glucocorticoid receptor (GR) signaling, interleukin-1 alpha (IL-1α), IL-1 receptor antagonist (IL-1Ra), NF-κB
Date Deposited: 16 Sep 2024 19:08
Last Modified: 16 Sep 2024 19:08
URI: http://d-scholarship.pitt.edu/id/eprint/45965

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