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RIPK1 down-regulation promotes tumor progression while enhancing the apoptotic response to TLR3 ligand in head and neck squamous cell carcinoma

McCormick, Kevin Dylan (2016) RIPK1 down-regulation promotes tumor progression while enhancing the apoptotic response to TLR3 ligand in head and neck squamous cell carcinoma. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Head and neck squamous cell carcinoma (HNSCC) is the most frequent malignancy of the aerodigestive tract and the limitations in current chemotherapeutic approaches have yielded a poor prognosis. Synthetic double stranded (ds) RNA, which activate toll-like receptor 3 (TLR3) and generate interferon regulatory factor 3 (IRF3)-mediated proapoptotic responses in cancer cells, are being investigated as potent adjuvants to chemotherapy. We had previously shown that cells derived from metastatic HNSCC were unable to activate prosurvival NF-κB in response to TLR3 ligand, resulting in an enhanced apoptotic response compared to cells from primary tumors. Here, we demonstrate that in metastatic tumor-derived cell lines, transcriptional downregulation of receptor interacting protein kinase 1 (RIPK1), an adaptor protein of the TLR3 pathway, enhances dsRNA-mediated apoptosis due to a loss of NF-κB activation. This is consistent with our observations supporting the reduction of RIPK1 expression during the tumor progression of HNSCC correlated with an increased promoter methylation in matched tumor samples from HNSCC patients. Treatment of metastatic tumor-derived cell lines with a hypomethylating agent rescued the expression of RIPK1, demonstrating that promoter methylation may be responsible for the downregulation of RIPK1. We show that silencing of RIPK1 enhances the tumor promoting properties in HNSCC cell lines by increasing the rate of migration, EGFR expression and anoikis resistance. As the downregulation of RIPK1 expression contributes to the metastatic phenotype of HNSCC, but is essential for TLR3-NF-κB mediated pro-survival responses, we believe the results described here may open new prospects for using synthetic dsRNA to target metastatic tumor cells. In light of these findings, RIPK1 downregulation as a treatment biomarker, or combinational therapies with NF-κB-signaling inhibitors, could be used to enhance the immunotherapeutic efficacy of synthetic dsRNA. As the downregulation of RIPK1 has been observed in additional carcinomas, our findings suggest that synthetic dsRNA could be used as a broad anti-cancer therapy and that RIPK1 expression can be a useful indicator to predict the therapy response.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
McCormick, Kevin Dylankdm32@pitt.eduKDM32
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSarkar, Saumendra Nsaumen@pitt.eduSAUMEN
Committee MemberCoyne, Carolyn Bcoynec2@pitt.eduCOYNEC2
Committee MemberKalinski, Pawelpak5@pitt.eduPAK5
Committee MemberKhan, Saleem AKhan@pitt.eduKHAN
Committee MemberYu, JianYuj2@upmc.eduJIY3
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Date: 7 May 2016
Date Type: Publication
Defense Date: 11 February 2016
Approval Date: 7 May 2016
Submission Date: 6 May 2016
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 168
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: TLR3 dsRNA RIPK1 NF-kB poly(I):poly(C)
Date Deposited: 08 May 2016 03:17
Last Modified: 19 Dec 2016 14:43


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