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Title page for ETD etd-10022011-214925


Type of Document Dissertation
Author Thu, Yee Mon
URN etd-10022011-214925
Title The role of NF-kB inducing kinase (NIK) in modulating melanoma tumorigenesis
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Josiean Eid Committee Chair
Ann Richmond Committee Member
Keywords
  • melanoma
  • cancer
  • NF-kB inducing kinase
  • NF-kB
Date of Defense 2011-09-21
Availability unrestricted
Abstract

Nuclear factor-B (NF-B) inducing kinase (NIK) is a MAP3K that regulates activation of NF-B. NIK is often over-expressed in tumor cells, including melanoma, but the significance of this in melanoma progression remains unclear. Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), primary (n=15) and metastatic melanoma (n=13) lesions showed a statistically significant elevation in NIK expression when compared to benign nevi (n=30). Depletion of NIK using shRNA in melanoma cell lines decreased proliferation, increased apoptosis, delayed cell cycle progression, and reduced tumor growth in a mouse xenograft model. Consistent with the previous studies, NIK deficiency reduced activation of the non-canonical NF-B pathway, while canonical NF-B activation remained intact. NIK depletion also reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, as well as pro-survival factors BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-B pathway. Shown here for the first time is the demonstration that NIK depletion decreases -catenin mediated transcription to down-regulate expression of survivin as well as other -catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate NIK mediates both -catenin and NF-B regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma. In addition, novel NIK-interacting proteins were identified by using mass spectrometry analysis. Some of these proteins include heat shock protein 90 (Hsp90), ribosomal protein S3 (RPS3) and DEAD box polypeptide 5 (DDX5).

Inhibitor of IB kinase (IKK), another kinase of NF-B pathway, also contributes to melanoma growth. Systemic inhibition of this kinase in a melanoma xenograft model was characterized using a pharmacological IKK inhibitor, BMS-345541. Results show that inhibition of IKK alters the host immune cell composition and the composition of leukocytes infiltrating tumor, suggesting that systemic NF-B inhibition should be evaluated more carefully before going forward as a cancer therapy.

In this research, I identified NIK as a new potential target for melanoma growth, revealed important new biological functions of NIK, and unraveled key effects of IKK inhibition on the tumor microenvironment.

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