UBC Theses and Dissertations
The role of nuclear factor kappaB subunit p50 melanoma pathogenesis Gao, Kai
Transcriptional factor NF-κB family has been demonstrated 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-κB members, which would provide the basis for the selective blockade and reduction of therapeutic side effects resulting from unspecific inhibition of NF-κB members. We firstly explored the role of NF-κB p105/p50 in melanoma pathogenesis in vivo. We found that the expression of NF-κB p105/p50 significantly increased in dysplastic nevi, primary melanoma and metastatic melanoma compared to normal nevi (p=0.0004, χ²test). NF-κB p105/p50 nuclear staining increased with melanoma progression and strong NF-κB 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-κB p105/p50 is an independent prognostic factor in this subgroup. Moreover, we found that upregulation of NF-κB p50 enhanced melanoma cell migration whereas siRNA knockdown inhibited cell migration.. In addition, overexpression of NF-κB p50 induced RhoA activity and Rock-mediated formation of stress fiber in melanoma cells. To further elucidate how NF-κB p50 is involved in melanoma, we analyzed the gene expression profile in melanoma cells overexpressing NF-κB p50 by cDNA microarray. We found that IL-6 mRNA was highly induced by NF-κB p50. Since IL-6 is a newly reported proangiogenic factor in cancer, we hypothesized that NF-κB p50 could promote melanoma angiogenesis by upregulating IL-6. Indeed, using the proliferation assay of human umbilical vein endothelial cells (HUVECs) we demonstrated that the conditioned medium from melanoma cells overexpressing NF-κB p50 promoted HUVEC proliferation in vitro. In vivo matrigel plug assay showed that tumor vascularity was significantly enhanced by NF-κB p50. Furthermore, silence of NF-κB p105/p50 decreased IL-6 expression and overexpression of ATF3 abrogated the effect of NF-κB p50 on the induction of IL-6. Taken together, our data indicate that NF-κB p105/p50 may be an important marker for human melanoma progression and prognosis as well as a potentially selective therapeutic target.
Item Citations and Data