Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer

Fukui, Takayuki; Kondo, Masashi; Ito, Genshi; Maeda, Osamu; Sato, N.; Yoshioka, Hide; Yokoi, Kohei; Ueda, Yuichi; Shimokata, Kaoru; Sekido, Yoshitaka

doi:10.1038/sj.onc.1208777

Cited by 153 publications

(122 citation statements)

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“…Because none of the breast cancer cell lines presented aberrant TCF/LEF transcription, we used an expression vector encoding a b-catenin mutant to boost Wnt signalling. We found that the TCF/LEF transcriptional activity induced by the mutant b-catenin was synergistically upregulated when combined with SFRP1 depletion, which is consistent with the recent observation by Fukui et al (2005). Using non-small-cell lung carcinoma cells in which SFRP1 was methylated, they showed that when SFRP1 was cotransfected with mutant b-catenin, SFRP1 could attenuate TCF/LEF activity induced by exogenous b-catenin.…”

Section: Genetics and Genomicssupporting

confidence: 91%

“…Consistent with that idea, we have previously found that SFRP1 is methylated in several breast cancer cell lines (Suzuki et al, 2002), and two other groups recently reported frequent SFRP1 methylation in both primary and cultured breast cancer cells (Lo et al, 2006;Veeck et al, 2006). To date, epigenetic silencing of SFRP1 has been identified in a variety of malignancies, including cancers of the bladder (Stoehr et al, 2004), prostate (Lodygin et al, 2005), lung (Fukui et al, 2005) and breast, although abnormalities involving other SFRP family genes are largely unexplored.We previously showed that SFRP1, SFRP2 and SFRP5 are frequently inactivated in CRC and gastric cancer (GC) (Suzuki et al, 2002;Nojima et al, 2007), and that SFRPs suppress constitutive Wnt signalling when overexpressed in CRC and GC cells. Similarly, Bafico et al (2004) reported that constitutive Wnt signalling could be suppressed in breast cancer cells by SFRP1 and DKK1.…”

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confidence: 71%

supporting

confidence: 71%

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Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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Although mutation of APC or CTNNB1 (b-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a b-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. British Journal of Cancer (2008) Wnt ligands are secreted proteins that bind to transmembrane receptors in the Frizzled (Fz) family. During normal developmental processes, the resultant Wnt signalling plays essential roles in the regulation of cell proliferation, patterning and fate determination (Cadigan and Nusse, 1997). The binding of Wnt to Fz leads to dephosphorylation and stabilisation of b-catenin, enabling it to be translocated into the nucleus, where it interacts with members of the T-cell factor/lymphocyte enhancer factor (TCF/LEF) family of transcription factors to stimulate the expression of target genes. This signalling pathway is strongly implicated in tumorigenesis; indeed, the first mammalian Wnt isoform was identified based on its ability to promote mouse mammary tumorigenesis (Polakis, 2000). In addition, aberrant nuclear and cytoplasmic localisation of b-catenin is frequently observed in human breast cancer (Lin et al, 2000;Ryo et al, 2001;Chung et al, 2004). In contrast to colorectal cancer (CRC), however, mutation of APC, AXIN or CTNNB1 (b-catenin) is rare in breast cancer, indicating that other mechanisms are responsible for the activation of b-catenin. These mechanisms could include increased expression of Wnt ligand (Huguet et al, 1994;Dale et al, 1996;Bui et al, 1997) and/or the loss of Wnt antagonists.Several classes of secreted Wnt antagonists are known, including the Cerberus, Wnt inhibitory factor 1, secreted frizzled-related protein (SFRP) and the Dickkopf (DKK) families (Kawano and Kypta, 2003). The SFRP family is comprised of five secreted glycopr...

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Section: Genetics and Genomicssupporting

confidence: 91%

supporting

confidence: 71%

supporting

confidence: 71%

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Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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“…Interestingly, sFRP1 functions as a negative regulator of the Wnt pathway and blocks the activation of the downstream target genes (Kawano and Kypta, 2003). Downregulation of the sFRP1 has been found in a variety of malignancies including colon (Caldwell et al, 2004), breast (Veeck et al, 2006), bladder (Stoehr et al, 2004), ovarian (Takada et al, 2004), and lung (Fukui et al, 2005) cancers. It has been reported that reconstitution of sFRP1 inhibits HCC growth in vitro and in vivo, and the sFRP1 restoration offers a potential therapeutic approach for treatment of HCC (Hu et al, 2009;Jiang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Decrease in the sFRP1 expression due to promoter hypermethylation may result in the activation of the Wnt pathway and consequent tumor development. Interestingly, reduced expression of sFRP1 has been found in many malignancies, including colorectal (Caldwell et al, 2004;Suzuki et al, 2004), lung (Fukui et al, 2005), ovarian (Takada et al, 2004), breast (Veeck et al, 2006), esophageal (Zou et al, 2005;Clement et al, 2006), and liver (Shih et al, 2006) cancers.…”

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confidence: 99%

Involvement of genetic instability in the downregulation of sFRP1 in Chinese patients with hepatocellular carcinoma

Qiu

Zhou³

et al. 2010

The Anatomical Record

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Secreted frizzled-related protein 1 (sFRP1) is a new tumor suppressor based on recent researches, but the correlation of the genetic instability of sFRP1 gene with the clinicopathologic features of the hepatocellular carcinoma (HCC) has not been studied in Chinese people. In this study, 42 pairs of paraffin-embedded HCC and adjacent non-carcinoma tissues were examined for the loss of heterozygosity (LOH) and microsatellite instability (MSI) of two microsatellite markers D8S532 and D8S1722 located in the vicinity of the sFRP1 gene. Envision immunohistochemistry was used to assess the expression of sFRP1. We found that the reduced expression of the sFRP1 protein was frequently observed in Chinese patients with HCC, which may at least partially result from the genetic instability, especially LOH. The LOH-associated sFRP1 downregulation may play an important role in the development of HCC. Anat Rec, 293:2020Rec, 293: -2026Rec, 293: , 2010.

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Wnt antagonist gene polymorphisms and renal cancer

Hirata

Hinoda

Nakajima

et al. 2009

Cancer

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Purpose Epigenetic silencing of several Wnt pathway related genes has been reported in renal cancer. Except for the TCF4 gene, there are no reports regarding Wnt pathway gene polymorphisms in renal cancer. Therefore, we hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer. Experimental Design A total of 210 patients (145 male and 65 female) with pathologically confirmed renal cell carcinoma (RCC), and 200 age- and sex-matched control individuals were enrolled in this study. We genotyped 14 SNPs in six genes including DKK2 (rs17037102, rs419558, rs447372), DKK3 (rs3206824, rs11022095, rs1472189, rs7396187, rs2291599), DKK4 (rs2073664), sFRP4 (rs1802073, rs1802074), SMAD7 (rs12953717), DAAM2 (rs6937133, rs2504106) using PCR-RFLP and direct sequencing in RCC and age-matched healthy subjects. We also tested the relationship between these polymorphisms and clinicopathologic data including gender, grade, tumor stage, lymph-node involvement, distant metastasis, and overall survival. Results A significant decrease in the frequency of the G/A+A/A genotypes in the DKK3 codon335 rs3206824 was observed in RCC patients compared with controls. The frequency of the rs3206824 (G/A) A- rs7396187 (G/C) C haplotype was significantly lower in RCC compared with other haplotypes. We also found that DKK3 rs1472189 C/T is associated with distant metastasis and furthermore, DKK2 rs17037102 G homozygous patients had a decreased risk for death by multivariate Cox regression analysis. Conclusions This is the first report documenting that DKK3 polymorphisms are associated with RCC and that the DKK2 rs17037102 polymorphism may be a predictor for survival in RCC patients after radical nephrectomy.

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Transcriptional silencing of secreted frizzled related protein 1 (SFRP1) by promoter hypermethylation in non-small-cell lung cancer

Cited by 153 publications

References 23 publications

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Involvement of genetic instability in the downregulation of sFRP1 in Chinese patients with hepatocellular carcinoma

Wnt antagonist gene polymorphisms and renal cancer

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