Prognostic significance of nuclear factor-kappaB p105/p50 in human melanoma and its role in cell migration.
Transcriptional factor nuclear factor-kappaB (NF-kappaB) family has been shown to play an important role in tumor pathogenesis and serve as a potential target in cancer therapy. However, it is necessary to clarify the specific functions of NF-kappaB members, which would provide the basis for the selective blockade and reduction of therapeutic side effects resulting from unspecific inhibition of NF-kappaB members. In this study, we explored the role of NF-kappaB p105/p50 in melanoma pathogenesis in vitro and in vivo. We found that the expression of NF-kappaB p105/p50 significantly increased in dysplastic nevi, primary melanoma, and metastatic melanoma compared with normal nevi (P = 0.0004, chi(2) test). Furthermore, NF-kappaB p105/p50 nuclear staining increased with melanoma progression and strong NF-kappaB p105/p50 nuclear staining was inversely correlated with disease-specific 5-year survival of patients with tumor thickness >2.0 mm (P = 0.014, log-rank test). Multivariate Cox regression analysis revealed that nuclear expression of NF-kappaB p105/p50 is an independent prognostic factor in this subgroup. Moreover, we found that up-regulation of NF-kappaB p50 enhanced melanoma cell migration, whereas small interfering RNA knockdown inhibited cell migration. In addition, overexpression of NF-kappaB p50 induced RhoA activity and Rock-mediated formation of stress fiber in melanoma cells. Taken together, our data indicate that NF-kappaB p105/p50 may be an important marker for human melanoma progression and prognosis as well as a potentially selective therapeutic target.
Gao
Kai
K
Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Dai
Derek L
DL
Martinka
Magdalena
M
Li
Gang
G
D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D014157:Transcription Factors