Frequent epigenetic inactivation of Wnt inhibitory factor-1 in human gastrointestinal cancers View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2005-07-11

AUTHORS

Hiroaki Taniguchi, Hiroyuki Yamamoto, Tamaki Hirata, Nobuki Miyamoto, Mariko Oki, Katsuhiko Nosho, Yasushi Adachi, Takao Endo, Kohzoh Imai, Yasuhisa Shinomura

ABSTRACT

Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Wnt antagonists have recently attracted wide attention. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind to Wnt proteins directly and inhibit Wnt signaling pathway. It has been reported that WIF-1 expression is down regulated in several solid tumors and that WIF-1 is silenced by promoter hypermethylation in lung and colorectal cancer. By using RT–PCR, bisulfite sequence analysis, and methylation-specific PCR, we analysed expression and methylation of WIF-1 in cancer cell lines and freshly resected cancer tissues of the esophagus, stomach, colorectum, and pancreas. Downregulation of WIF-1 mRNA expression was observed in 61 (91.0%) of 67 cancer cell lines, 16 (80.0%) of 20 esophageal, 23 (74.2%) of 31 gastric, 41 (82.0%) of 50 colorectal, and six (75.0%) of eight pancreatic cancer tissues. Downregulation of WIF-1 expression was also observed at protein level. No significant association between WIF-1 downregulation and clinicopathological characteristics was found, suggesting that downregulation of WIF-1 expression is an early event in carcinogenesis of these cancers. Indeed, downregulation of WIF-1 expression was observed in 32 (72.7%) of 44 colorectal adenoma tissues and 18 (78.2%) of 23 early mucosal or submucosal colorectal carcinoma tissues. CpG island hypermethylation in the WIF-1 promoter region correlated with downregulation of WIF-1 expression in cancer cell lines and tissues. Treatment with demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), restored WIF-1 expression in cancer cell lines. A combined treatment of 5-aza-dC and a histone deacetylase inhibitor, trichostatinA, restored WIF-1 expression synergistically, indicating the role of cytosine methylation and histone deacetylation in the silencing of the WIF-1 gene. Transfection of the WIF-1 gene construct into TE-1 esophageal cancer cell lines or SW48 colon cancer cell lines lacking WIF-1 expression resulted in a significant inhibition on colony formation, cell proliferation, anchorage-independent growth in soft agar. TOPflash assay showed WIF-1 inhibits Wnt canonical signaling in these cell lines. These results suggest tumor suppressive function of WIF-1, due to its ability to inhibit Wnt signaling. Our results suggest that WIF-1 silencing due to promoter hypermethylation is an important mechanism underlying aberrant activation of the Wnt signaling pathway in carcinogenesis of the digestive organs. Modulation of the Wnt pathway, through reversal of WIF-1 silencing by demethylating agents, is a potential target for treatment and/or prevention of gastrointestinal cancers. More... »

PAGES

7946-7952

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1208910

DOI

http://dx.doi.org/10.1038/sj.onc.1208910

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1019406107

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16007117


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28 schema:description Aberrant activation and upregulation of the Wnt pathway is a key feature of many cancers. Wnt antagonists have recently attracted wide attention. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind to Wnt proteins directly and inhibit Wnt signaling pathway. It has been reported that WIF-1 expression is down regulated in several solid tumors and that WIF-1 is silenced by promoter hypermethylation in lung and colorectal cancer. By using RT–PCR, bisulfite sequence analysis, and methylation-specific PCR, we analysed expression and methylation of WIF-1 in cancer cell lines and freshly resected cancer tissues of the esophagus, stomach, colorectum, and pancreas. Downregulation of WIF-1 mRNA expression was observed in 61 (91.0%) of 67 cancer cell lines, 16 (80.0%) of 20 esophageal, 23 (74.2%) of 31 gastric, 41 (82.0%) of 50 colorectal, and six (75.0%) of eight pancreatic cancer tissues. Downregulation of WIF-1 expression was also observed at protein level. No significant association between WIF-1 downregulation and clinicopathological characteristics was found, suggesting that downregulation of WIF-1 expression is an early event in carcinogenesis of these cancers. Indeed, downregulation of WIF-1 expression was observed in 32 (72.7%) of 44 colorectal adenoma tissues and 18 (78.2%) of 23 early mucosal or submucosal colorectal carcinoma tissues. CpG island hypermethylation in the WIF-1 promoter region correlated with downregulation of WIF-1 expression in cancer cell lines and tissues. Treatment with demethylating agent, 5-aza-2′-deoxycytidine (5-aza-dC), restored WIF-1 expression in cancer cell lines. A combined treatment of 5-aza-dC and a histone deacetylase inhibitor, trichostatinA, restored WIF-1 expression synergistically, indicating the role of cytosine methylation and histone deacetylation in the silencing of the WIF-1 gene. Transfection of the WIF-1 gene construct into TE-1 esophageal cancer cell lines or SW48 colon cancer cell lines lacking WIF-1 expression resulted in a significant inhibition on colony formation, cell proliferation, anchorage-independent growth in soft agar. TOPflash assay showed WIF-1 inhibits Wnt canonical signaling in these cell lines. These results suggest tumor suppressive function of WIF-1, due to its ability to inhibit Wnt signaling. Our results suggest that WIF-1 silencing due to promoter hypermethylation is an important mechanism underlying aberrant activation of the Wnt signaling pathway in carcinogenesis of the digestive organs. Modulation of the Wnt pathway, through reversal of WIF-1 silencing by demethylating agents, is a potential target for treatment and/or prevention of gastrointestinal cancers.
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34 schema:keywords CpG island hypermethylation
35 Frequent epigenetic inactivation
36 PCR
37 RT-PCR
38 SW48 colon cancer cell line
39 TOPflash
40 WIF-1
41 WIF-1 expression
42 WIF-1 gene
43 WIF-1 mRNA expression
44 WIF-1 promoter region
45 Wnt
46 Wnt inhibitory factor 1
47 Wnt pathway
48 Wnt proteins
49 aberrant activation
50 ability
51 activation
52 adenoma tissue
53 agar
54 agents
55 analysis
56 anchorage-independent growth
57 antagonist
58 association
59 attention
60 bisulfite sequence analysis
61 cancer
62 cancer cell lines
63 cancer tissues
64 canonical signaling
65 carcinogenesis
66 carcinoma tissues
67 cell lines
68 cell proliferation
69 characteristics
70 clinicopathological characteristics
71 colon cancer cell lines
72 colony formation
73 colorectal
74 colorectal adenoma tissues
75 colorectal cancer
76 colorectal carcinoma tissues
77 colorectum
78 constructs
79 cytosine methylation
80 deacetylase inhibitors
81 deacetylation
82 demethylating agent
83 digestive organs
84 downregulation
85 early events
86 epigenetic inactivation
87 esophageal
88 esophageal cancer cell lines
89 esophagus
90 events
91 expression
92 factor 1
93 features
94 formation
95 function
96 gastric
97 gastrointestinal cancer
98 gene constructs
99 genes
100 growth
101 histone deacetylase inhibitors
102 histone deacetylation
103 human gastrointestinal cancers
104 hypermethylation
105 important mechanism
106 inactivation
107 inhibition
108 inhibitors
109 inhibitory factor 1
110 inhibits
111 island hypermethylation
112 key features
113 levels
114 lines
115 lung
116 mRNA expression
117 mechanism
118 methylation
119 methylation-specific PCR
120 modulation
121 organs
122 pancreas
123 pancreatic cancer tissues
124 pathway
125 potential target
126 prevention
127 proliferation
128 promoter hypermethylation
129 promoter region
130 protein
131 protein levels
132 region
133 results
134 reversal
135 role
136 sequence analysis
137 signaling
138 significant association
139 significant inhibition
140 silencing
141 soft agar
142 solid tumors
143 stomach
144 suppressive function
145 target
146 tissue
147 transfection
148 treatment
149 trichostatinA
150 tumor suppressive function
151 tumors
152 upregulation
153 wide attention
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