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Frequent Epigenetic Inactivation of SFRP Genes and Constitutive Activation of Wnt Signaling in Gastric Cancer

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Frequent Epigenetic Inactivation of SFRP Genes and Constitutive Activation of Wnt Signaling in Gastric Cancer Oncogene (2007) 26, 4699–4713 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer M Nojima1,8, H Suzuki1,2,8, M Toyota1,3,4, Y Watanabe5, R Maruyama1, S Sasaki1, Y Sasaki3, H Mita3, N Nishikawa6, K Yamaguchi6, K Hirata6, F Itoh5, T Tokino3, M Mori2, K Imai7 and Y Shinomura1 1First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; 2Department of Public Health, Sapporo Medical University, Sapporo, Japan; 3Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan; 4PRESTO JST, Kawaguchi, Japan; 5Division of Gastroenterology and Hepatology, Department of Internal Medicine, St Marianna University School of Medicine, Kasawaki, Japan; 6First Department of Surgery, Sapporo Medical University, Sapporo, Japan and 7Sapporo Medical University, Sapporo, Japan Activation of Wnt signaling has been implicated in gastric Introduction tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (b-catenin) and AXIN are seen The two known Wnt signaling pathways play essential much less frequently in gastric cancer (GC) than in roles in the regulation of cell proliferation, patterning colorectal cancer. In the present study, we investigated and fate determination during normal developmen- the relationship between activation of Wnt signaling tal processes (Taketo, 2004). The canonical pathway and changes in the expression of secreted frizzled-related operates by stabilizing b-catenin, whereas the non- protein (SFRP) family genes in GC. We frequently canonical pathway does not require b-catenin signaling observed nuclear b-catenin accumulation (13/15; 87%) and controls cell movement during morphogenesis. and detected the active formof b-catenin in most (12/16; When the Wnt pathway is in its resting state, b-catenin 75%) GC cell lines. CpG methylation-dependent silenc- is phosphorylated by glycogen synthase kinase 3b ing of SFRP1, SFRP2 and SFRP5 was frequently seen (GSK3b) within a protein complex that also includes among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/ casein kinase 1, adenomatous polyposis coli (APC) and 16, 100%; SFRP5, 13/16, 81%) and primary GC Axin (Gregorieff and Clevers, 2005). Phosphorylated b- specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; catenin is immediately degraded via the ubiquitin SFRP5, 30/46, 65%), and treatment with the DNA proteasome pathway. Wnt binding to Frizzled (Fz) methyltransferase inhibitor 5-aza-20-deoxycytidine rapidly results in the activation of Dishevelled (Dsh), which restored SFRP expression. Ectopic expression of SFRPs inhibits the activity of GSK3b, resulting in dephos- downregulated T-cell factor/lymphocyte enhancer factor phorylation and stabilization of b-catenin, enabling it to transcriptional activity, suppressed cell growth and accumulate within the nucleus, where it interacts with induced apoptosis in GC cells. Analysis of global expression members of the T-cell factor/lymphocyte enhancer revealed that overexpression of SFRP2 repressed Wnt factor (TCF/LEF) family of transcription factors to target genes and induced changes in the expression of stimulate the expression of target genes (Taketo, 2004). numerous genes related to proliferation, growth and The Wnt/b-catenin pathway is known to be involved apoptosis in GC cells. It thus appears that aberrant SFRP in tumorigenesis involving several cell types. For methylation is one of the major mechanisms by which Wnt instance, the first mammalian Wnt isoform was identi- signaling is activated in GC. fied based on its ability to promote mouse mammary Oncogene (2007) 26, 4699–4713; doi:10.1038/sj.onc.1210259; tumorigenesis. APC is mutated in the germ line of published online 5 February 2007 individuals with familial adenomatous polyposis coli, and acquired mutations in APC, CTNNB1 (b-catenin) Keywords: SFRP; methylation; gastric cancer; Wnt or AXIN2 initiate the majority of sporadic colorectal signaling; apoptosis cancers (CRCs) (Gregorieff and Clevers, 2005), at least in part because mutant APC and Axin are unable to assist GSK3b in phosphorylating/inactivating b-catenin. Similarly, mutations that lead to amino-acid substitu- tion of the phosphorylated residues of b-catenin stabilize Correspondence: Dr H Suzuki, First Department of Internal Medicine, the protein. Either of these disruptions can lead to Sapporo Medical University, S1, W16, Chuo-Ku, Sapporo 060-8543, constitutive activation of the Wnt pathway. Japan. Secreted frizzled-related proteins (SFRPs) are a E-mail: [email protected] 8These authors contributed equally to this work. family of five secreted glycoproteins that have been Received 17 February 2006; revised 24 November 2006; accepted 4 December identified as modulators of the Wnt signaling pathway 2006; published online 5 February 2007 (Jones and Jomary, 2002). SFRP family members all SFRPs methylation in gastric cancer M Nojima et al 4700 contain an N-terminal domain homologous to the in APC or CTNNB1 are not often found in sporadic cysteine-rich domain (CRD) of the Wnt receptor Fz GC. For instance, our group previously examined 35 and a C-terminal domain with some homology to netrin. primary GC tissue samples and found no mutations in In contrast to Fz family proteins, SFRPs lack a exon 3 of CTNNB1, whereas nuclear and cytoplasmic transmembrane region and the cytoplasmic domain localization of b-catenin was observed in 23% of the required for signal transduction into the cells. This tumors (Sasaki et al., 2001). In the present study, enables SFRPs to downregulate Wnt signaling by therefore, our aim was to clarify the respective roles competing with Fz for Wnt binding via its CRD domain played by Wnt signaling and changes in SFRP expres- or by binding directly to Fz (Jones and Jomary, 2002). sion in GC. Up to now, it has been thought that mutations in APC, AXIN or CTNNB1 can cause constitutive signal- ing independent of the upstream signal from Wnt. In addition, we and others recently showed that SFRP Results family genes are frequent targets of aberrant DNA methylation in CRCs (Suzuki et al., 2002; Caldwell Frequent activation of the canonical Wnt signaling et al., 2004), and we further showed that restoration of pathway in GC SFRP1, SFRP2 and SFRP5 in CRC cells attenuates To investigate the Wnt signaling status in GC, we Wnt signaling, even in the presence of downstream initially analysed endogenous expression of b-catenin, as mutations (Suzuki et al., 2004). Since then, down- it is well known that canonical Wnt signaling allows regulation and methylation of SFRP genes have been stabilization of b-catenin and its accumulation in the identified in a variety of malignancies, including bladder nucleus (Taketo, 2004). Immunofluorescent analysis cancer (Stoehr et al., 2004), prostate cancer (Lodygin of the cellular distribution of endogenous b-catenin et al., 2005), endometrial cancer (Risinger et al., 2005), revealed nuclear accumulation of the protein in 13 of 15 lung cancer (Fukui et al., 2005), breast cancer (Veeck (87%) GC cells examined, whereas only six cells showed et al., 2006), mesothelioma (Lee et al., 2004) and chronic a membranous staining pattern (Table 1; Figure 1a). lymphocytic leukemia (Liu et al., 2006), which strongly Moreover, Western analysis using an anti-b-catenin suggests SFRPs function as tumor suppressor genes. antibody revealed detectable levels of endogenous b- Gastric cancer (GC) is the second most common catenin in all of the GC cell lines tested (Figure 1b). cause of death from cancer among both men and women Because activation of Wnt signaling leads to activation in the world. Wnt signaling is involved in cell prolifera- of b-catenin, we also utilized an antibody specific for tion during development of the gut, and activation of the active form of b-catenin, which is dephosphorylated the Wnt signaling pathway has been implicated in on Ser37 and Thr41. We detected active b-catenin in 12 gastric tumorigenesis (Yuasa, 2003). Indeed, persons of 16 cells, although the levels of expression varied carrying a germ-line mutation in APC have a 10-fold considerably among the cell lines (Figure 1b; Table 1). greater risk of developing GC than those without the When we then analysed TCF/LEF-regulated transcrip- mutation (Offerhaus et al., 1992). However, mutations tional activity in GC cells using a TCF/LEF-responsive Table 1 Summary of Wnt signaling analysis results, APC and CTNNB1 status, expression and methylation status of SFRPs in GC cell lines b-Catenin staining Active-b-catenin TCF activity Genetic alterations Expression status Methylation status (OT/OF) Nuclear Membranous APC b-Catenin SFRP1 SFRP2 SFRP5 SFRP1 SFRP2 SFRP5 MKN1 + ÀÀ0.74 Wild Wild ÀÀ+M M U MKN7 ++ À +++ 2.31 Wild Wild ÀÀÀMMM MKN74 ++ + +++ 9.94 Mutant Wild ÀÀÀMMM SH101 ++ À + 1.83 Wild Wild ÀÀÀMMU SNU1 ++ ÀÀ0.33 Wild Wild ÀÀÀU/M U/M M SNU638 ++ À + 6.94 Wild Mutant ÀÀÀM M U/M KatoIII + À +++ 97.4 Wild Amplified ÀÀÀ+a MMM JRST ++ À ++ 3.28 Wild Wild ÀÀÀM M U/M AZ521 + ++ ++ NAb Mutant Wild ÀÀÀMMM MKN28 À + + 0.91 Wild Wild ÀÀÀMMM MKN45 + + ++ 1.67 Wild Wild ÀÀÀMMM NUGC3 + ++ + 1.17 Wild Wild ÀÀ+ M M U/M NUGC4 À + À 2.54 NA NA ÀÀ+M M U AGS ++ À ++ 39.1 Wild Mutant ÀÀÀMMM NCI-N87 ++ ÀÀ1.73 Wild Wild ÀÀÀMMM SNU16 ND ND + ND Wild Wild ÀÀÀU/M U/M U/M Abbreviations: APC, adenomatous polyposis coli; GC, gastric cancer; M, methylated; NA, not available; ND, not done; RT–PCR, reverse transcriptase–polymerase
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