Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma.
WIF-1 is a negative regulator of the Wnt-signaling pathway that may have important implications for tumorigenesis. Microarray analysis of whole genome expression in mesothelioma tissue revealed down-regulation of 491 genes and up-regulation of 167 genes involved mainly in Jak-STAT signaling (8 genes), MAPK signaling (16 genes) and Wnt signaling (13 genes) pathways. Of these, WIF-1 gene was down-regulated in mesothelioma 72-fold compared to normal tissue. We also analyzed WIF-1 and SFRPs promoter methylations in 46 mesothelioma tissues, 8 mesothelioma cell lines by methylation-specific polymerase chain reaction (MSP). WIF-1 promoter methylation was observed in 34 of 46 mesothelioma tissues (73.9%) and in all 8 mesothelioma cell lines. SFRP1, 2 and 4 promoter methylation was observed in 21 of 37 (56.8%), 26 of 42 (61.9%) and 17 of 36 (47.2%) mesothelioma tissues, respectively. Promoter methylation of any WIF-1 and/or SFRP genes was observed in 44 of 46 (95.6%) mesothelioma tissues. The treatment of mesothelioma cell lines with 5-aza-2'-deoxycytidine (5-aza-2dC) showed WIF-1 promoter methylation recovery followed by restoration of WIF-1 expression in 6 of 8 mesothelioma cell lines. The cytoplasmic expression of beta-catenin was observed in 38 of 43 cases of mesothelioma without any nuclear reactivity. The eight mesothelioma cell lines and 27 cases of mesothelioma examined showed no mutation in exon 3 of beta-catenin suggesting no alteration of canonical Wnt signaling pathway. Our data suggest that WIF-1 promoter methylation is a common event in mesothelioma.
Kohno
Hidekazu
H
Department of Pathology, Hiroshima University, Graduate School of Biomedical Sciences, Minami-ku, Hiroshima 734-8551, Japan.
Amatya
Vishwa Jeet
VJ
Takeshima
Yukio
Y
Kushitani
Kei
K
Hattori
Noboru
N
Kohno
Nobuoki
N
Inai
Kouki
K
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014407:Tumor Cells, Cultured; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118723:SFRP4 protein, human; C485569:WIF1 protein, human