Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model.
This study demonstrates that in malignant melanoma, elevated levels of nuclear beta-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of beta-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice. Genome-wide transcriptional profiling reveals that WNT3A up-regulates genes implicated in melanocyte differentiation, several of which are down-regulated with melanoma progression. These findings suggest that WNT3A can mediate transcriptional changes in melanoma cells in a manner reminiscent of the known role of Wnt/beta-catenin signaling in normal melanocyte development, thereby altering melanoma cell fate to one that may be less proliferative and potentially less aggressive. Our results may explain the observed loss of nuclear beta-catenin with melanoma progression in human tumors, which could reflect a dysregulation of cellular differentiation through a loss of homeostatic Wnt/beta-catenin signaling.
Chien
Andy J
AJ
Institute for Stem Cell and Regenerative Medicine, Department of Medicine, Division of Dermatology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Moore
Erin C
EC
Lonsdorf
Anke S
AS
Kulikauskas
Rima M
RM
Rothberg
Bonnie Gould
BG
Berger
Aaron J
AJ
Major
Michael B
MB
Hwang
Sam T
ST
Rimm
David L
DL
Moon
Randall T
RT
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016019:Survival Analysis; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism*
D015415:Biomarkers; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin