NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the Β-catenin pathway

Y. M. Thu, Y. Su, J. Yang, Ryan C Splittgerber, S. Na, A. Boyd, C. Mosse, C. Simons, A. Richmond

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Nuclear factor-B (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB. NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been 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 with benign nevi (n=30). Moreover, when short hairpin RNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model. As expected, when NIK was depleted there was decreased activation of the non-canonical NF-κB pathway, whereas canonical NF-κB activation remained intact. NIK depletion also resulted in reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, and pro-survival factors such as BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-κB pathway. Shown here for the first time is the demonstration that NIK modulates Β-catenin-mediated transcription to promote expression of survivin. NIK-depleted melanoma cells exhibited downregulation of survivin as well as other Β-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate that NIK mediates both Β-catenin and NF-κB regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma.

Original languageEnglish (US)
Pages (from-to)2580-2592
Number of pages13
JournalOncogene
Volume31
Issue number20
DOIs
StatePublished - May 17 2012

Fingerprint

Catenins
Melanoma
Carcinogenesis
Phosphotransferases
Growth
Tissue Array Analysis
Dysplastic Nevus Syndrome
Gene Expression
Neoplasms
Nevus
Heterografts
Small Interfering RNA
Cell Cycle
Down-Regulation

Keywords

  • NIK
  • melanoma
  • survival factors
  • tumorigenesis
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the Β-catenin pathway. / Thu, Y. M.; Su, Y.; Yang, J.; Splittgerber, Ryan C; Na, S.; Boyd, A.; Mosse, C.; Simons, C.; Richmond, A.

In: Oncogene, Vol. 31, No. 20, 17.05.2012, p. 2580-2592.

Research output: Contribution to journalArticle

Thu, YM, Su, Y, Yang, J, Splittgerber, RC, Na, S, Boyd, A, Mosse, C, Simons, C & Richmond, A 2012, 'NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the Β-catenin pathway', Oncogene, vol. 31, no. 20, pp. 2580-2592. https://doi.org/10.1038/onc.2011.427
Thu, Y. M. ; Su, Y. ; Yang, J. ; Splittgerber, Ryan C ; Na, S. ; Boyd, A. ; Mosse, C. ; Simons, C. ; Richmond, A. / NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the Β-catenin pathway. In: Oncogene. 2012 ; Vol. 31, No. 20. pp. 2580-2592.
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