Home LiteratureArticle Details
PMID: 19144919 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Activated Wnt/beta-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 106 ·No. 4 ·2009-01-27 ·Pages 1193-8

Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major MB, Hwang ST, Rimm DL, Moon RT

Abstract

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.

MeSH Terms
Animals Biomarkers/metabolism Cell Differentiation Cell Line, Tumor Cell Lineage Cell Nucleus/metabolism Cell Proliferation Disease Models, Animal Humans Melanocytes/metabolism,pathology Melanoma, Experimental/metabolism,pathology Mice Signal Transduction Skin Neoplasms/metabolism,pathology Survival Analysis Up-Regulation Wnt Proteins/metabolism Wnt3 Protein Wnt3A Protein beta Catenin/metabolism
Chemicals
Biomarkers WNT3A protein, human Wnt Proteins Wnt3 Protein Wnt3A Protein Wnt3a protein, mouse beta Catenin
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chien Andy J
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
Lonsdorf Anke S
Kulikauskas Rima M
Rothberg Bonnie Gould
Berger Aaron J
Major Michael B
Hwang Sam T
Rimm David L
Moon Randall T
References (53)
53 references, click to expand
  1. WNT and beta-catenin signalling: diseases and therapies.
    Nat Rev Genet. 2004 Sep;5(9):691-701 PMID: 15372092
  2. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells.
    Cancer Res. 2002 Dec 15;62(24):7328-34 PMID: 12499276
  3. A third-generation lentivirus vector with a conditional packaging system.
    J Virol. 1998 Nov;72(11):8463-71 PMID: 9765382
  4. Prognostic significance of cadherin-based adhesion molecules in cutaneous malignant melanoma.
    Cancer Epidemiol Biomarkers Prev. 2008 Apr;17(4):949-58 PMID: 18398036
  5. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.
    Science. 2007 May 18;316(5827):1043-6 PMID: 17510365
  6. Melastatin expression and prognosis in cutaneous malignant melanoma.
    J Clin Oncol. 2001 Jan 15;19(2):568-76 PMID: 11208852
  7. Prognostic significance of the wnt signalling pathway molecules APC, beta-catenin and E-cadherin in colorectal cancer: a tissue microarray-based analysis.
    Histopathology. 2007 Mar;50(4):453-64 PMID: 17448021
  8. Cytoplasmic and nuclear accumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma.
    Int J Cancer. 2001 Jun 15;92(6):839-42 PMID: 11351304
  9. Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors.
    Science. 2008 Apr 18;320(5874):365-9 PMID: 18420933
  10. Automated subcellular localization and quantification of protein expression in tissue microarrays.
    Nat Med. 2002 Nov;8(11):1323-7 PMID: 12389040
  11. Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway.
    Mol Cell Biol. 2002 Feb;22(4):1172-83 PMID: 11809808
  12. Mutational activation of the beta-catenin proto-oncogene is a common event in the development of Wilms' tumors.
    Cancer Res. 1999 Aug 15;59(16):3880-2 PMID: 10463574
  13. CD10 protein expression in tumor and stromal cells of malignant melanoma is associated with tumor progression.
    Mod Pathol. 2004 Oct;17(10):1251-8 PMID: 15205682
  14. Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1.
    Science. 1999 Sep 17;285(5435):1923-6 PMID: 10489374
  15. Beta-catenin in the melanocyte lineage.
    Pigment Cell Res. 2003 Jun;16(3):312-7 PMID: 12753406
  16. Defining the conditions for the generation of melanocytes from human embryonic stem cells.
    Stem Cells. 2006 Jul;24(7):1668-77 PMID: 16574754
  17. Stabilization of beta-catenin by genetic defects in melanoma cell lines.
    Science. 1997 Mar 21;275(5307):1790-2 PMID: 9065403
  18. Management of cutaneous melanoma.
    N Engl J Med. 2004 Sep 2;351(10):998-1012 PMID: 15342808
  19. Beta-catenin-induced melanoma growth requires the downstream target Microphthalmia-associated transcription factor.
    J Cell Biol. 2002 Sep 16;158(6):1079-87 PMID: 12235125
  20. Reduced beta-catenin expression in the cytoplasm of advanced-stage superficial spreading malignant melanoma.
    Clin Cancer Res. 2003 Aug 15;9(9):3383-8 PMID: 12960126
  21. Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression.
    PLoS One. 2007 Jul 04;2(7):e594 PMID: 17611626
  22. Prognostic and diagnostic significance of beta-catenin nuclear immunostaining in colorectal cancer.
    Clin Cancer Res. 2004 Feb 15;10(4):1401-8 PMID: 14977843
  23. Caught up in a Wnt storm: Wnt signaling in cancer.
    Biochim Biophys Acta. 2003 Jun 5;1653(1):1-24 PMID: 12781368
  24. WNT5A expression increases during melanoma progression and correlates with outcome.
    Clin Cancer Res. 2008 Sep 15;14(18):5825-32 PMID: 18794093
  25. Genetic and epigenetic alterations of the APC gene in malignant melanoma.
    Oncogene. 2004 Jul 1;23(30):5215-26 PMID: 15133491
  26. Importance of P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma.
    Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8606-14 PMID: 16361544
  27. Neural crest stem and progenitor cells.
    Annu Rev Cell Dev Biol. 2006;22:267-86 PMID: 16803431
  28. Nuclear beta-catenin accumulation as a prognostic factor in Dukes' D human colorectal cancers.
    Oncol Rep. 2004 Aug;12(2):245-51 PMID: 15254684
  29. Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development.
    Genes Dev. 2007 Nov 15;21(22):2923-35 PMID: 18006687
  30. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition.
    J Biol Chem. 2007 Jun 8;282(23):17259-71 PMID: 17426020
  31. WNTS and WNT receptors as therapeutic tools and targets in human disease processes.
    Front Biosci. 2007 Jan 01;12:448-57 PMID: 17127309
  32. Molecular classification of cutaneous malignant melanoma by gene expression profiling.
    Nature. 2000 Aug 3;406(6795):536-40 PMID: 10952317
  33. Structure, expression and chromosome mapping of MLZE, a novel gene which is preferentially expressed in metastatic melanoma cells.
    Jpn J Cancer Res. 2001 Feb;92(2):140-51 PMID: 11223543
  34. The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless.
    Cell. 1987 Aug 14;50(4):649-57 PMID: 3111720
  35. Frequent nuclear/cytoplasmic localization of beta-catenin without exon 3 mutations in malignant melanoma.
    Am J Pathol. 1999 Feb;154(2):325-9 PMID: 10027390
  36. Generation and analysis of melanoma SAGE libraries: SAGE advice on the melanoma transcriptome.
    Oncogene. 2004 Mar 18;23(12):2264-74 PMID: 14755246
  37. A Wnt-er wonderland--the complexity of Wnt signaling in melanoma.
    Cancer Metastasis Rev. 2005 Jun;24(2):237-50 PMID: 15986134
  38. Informatic selection of a neural crest-melanocyte cDNA set for microarray analysis.
    Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9277-80 PMID: 10430933
  39. The transcription network regulating melanocyte development and melanoma.
    Pigment Cell Res. 2004 Aug;17(4):318-25 PMID: 15250933
  40. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.
    Cancer Cell. 2002 Apr;1(3):279-88 PMID: 12086864
  41. Direct regulation of nacre, a zebrafish MITF homolog required for pigment cell formation, by the Wnt pathway.
    Genes Dev. 2000 Jan 15;14(2):158-62 PMID: 10652270
  42. The revised American Joint Committee on Cancer staging system for melanoma.
    Semin Oncol. 2002 Aug;29(4):361-9 PMID: 12170439
  43. Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC.
    Int J Cancer. 2002 Aug 10;100(5):549-56 PMID: 12124804
  44. When Wnts antagonize Wnts.
    J Cell Biol. 2003 Sep 1;162(5):753-5 PMID: 12952929
  45. Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma.
    J Cutan Pathol. 2006 Sep;33(9):599-607 PMID: 16965333
  46. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor.
    Science. 2007 Feb 2;315(5812):642-5 PMID: 17204608
  47. Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines.
    Melanoma Res. 2002 Apr;12(2):183-6 PMID: 11930117
  48. Melanoma stem cells: the dark seed of melanoma.
    J Clin Oncol. 2008 Jun 10;26(17):2890-4 PMID: 18539969
  49. A survival-stratification model of human colorectal carcinomas with beta-catenin and p27kip1.
    Cancer. 2002 Dec 15;95(12):2479-86 PMID: 12467060
  50. Loss of beta-catenin expression associated with disease progression in malignant melanoma.
    Br J Dermatol. 2001 Aug;145(2):210-6 PMID: 11531781
  51. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling.
    Dev Cell. 2003 Sep;5(3):367-77 PMID: 12967557
  52. Influence of the microenvironment on melanoma cell fate determination and phenotype.
    Cancer Res. 2006 Aug 15;66(16):7833-6 PMID: 16912153
  53. Down-regulation of the novel gene melastatin correlates with potential for melanoma metastasis.
    Cancer Res. 1998 Apr 1;58(7):1515-20 PMID: 9537257
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0811902106
Published
2009-01-27
Epub
2009-00-14
Pages
1193-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2626610
Subset
IM
Grants
Howard Hughes Medical Institute · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1073/pnas.0811902106 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2