<p>Nuclear factor-êB (NF-êB) inducing kinase (NIK) is a MAP3K that regulates activation of NF-êB. 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-êB pathway, while canonical NF-êB 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-êB pathway. Shown here for the first time is the demonstration that NIK depletion decreases â-catenin mediated transcription to down-regulate expression of survivin as well as other â-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate NIK mediates both â-catenin and NF-êB 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).
<p>Inhibitor of IêB kinase â (IKKâ), another kinase of NF-êB pathway, also contributes to melanoma growth. Systemic inhibition of this kinase in a melanoma xenograft model was characterized using a pharmacological IKKâ inhibitor, BMS-345541. Results show that inhibition of IKKâ alters the host immune cell composition and the composition of leukocytes infiltrating tumor, suggesting that systemic NF-êB inhibition should be evaluated more carefully before going forward as a cancer therapy.
<p>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 IKKâ inhibition on the tumor microenvironment.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-10022011-214925 |
| Date | 03 October 2011 |
| Creators | Thu, Yee Mon |
| Contributors | Josiean Eid, Ann Richmond |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-10022011-214925/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.002 seconds