Genetic and epigenetic alterations of the APC gene in malignant melanoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2004-05-10

AUTHORS

Jesper Worm, Claus Christensen, Kirsten Grønbæk, Eugene Tulchinsky, Per Guldberg

ABSTRACT

High levels of β-catenin and activating mutations in the β-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic β-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on β-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity. More... »

PAGES

5215-5226

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1207647

DOI

http://dx.doi.org/10.1038/sj.onc.1207647

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1020374172

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/15133491


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49 schema:description High levels of β-catenin and activating mutations in the β-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic β-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on β-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity.
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56 schema:keywords APC activity
57 APC gene
58 APC mutations
59 APC promoter 1A
60 APC promoter 1A hypermethylation
61 APC transcripts
62 CTNNB1 missense mutation
63 CTNNB1 mutations
64 Collectively
65 I. Collectively
66 RNA
67 TCF transactivation
68 Wnt
69 Wnt signalling-independent increase
70 activity
71 adenomatous polyposis coli (APC) gene
72 alleles
73 alterations
74 biopsy
75 capacity
76 catenin
77 catenin gene
78 catenin stability
79 catenin/T
80 cell factor
81 cell lines
82 cell proliferation
83 cells
84 coli gene
85 collagen type I. Collectively
86 components
87 contrast
88 corresponding wild-type allele
89 data
90 development
91 dose
92 effect
93 epigenetic alterations
94 epigenetic silencing
95 expression
96 expression of APC
97 factors
98 function
99 genes
100 growth
101 hairpin RNA
102 high levels
103 hypermethylation
104 implicating
105 increase
106 invasive capacity
107 invasive growth
108 key component
109 levels
110 lines
111 loss
112 malignancy
113 malignant melanoma
114 melanocytic cells
115 melanoma
116 melanoma biopsies
117 melanoma cell lines
118 melanoma cells
119 missense mutations
120 mutations
121 pathogenesis
122 pathway
123 polyposis coli gene
124 proliferation
125 promoter 1A
126 promoter 1A hypermethylation
127 promoter 1B.
128 residual APC activity
129 short hairpin RNA
130 signalling-independent increase
131 silencing
132 stability
133 stable expression
134 suppression
135 target genes
136 transactivation
137 transcription
138 transcripts
139 transduction pathways
140 truncating APC mutation
141 tumor-suppressive function
142 type I. Collectively
143 wild-type allele
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