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The role of nuclear factor kappaB subunit p50 melanoma pathogenesis Gao, Kai
Abstract
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 Metadata
Title |
The role of nuclear factor kappaB subunit p50 melanoma pathogenesis
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2007
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Description |
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.
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Genre | |
Type | |
Language |
eng
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Date Available |
2011-02-24
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0100714
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.