Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

Nojima, Masanori; Suzuki, Hiromu; Toyota, Minoru; Watanabe, Yoshiyuki; Maruyama, Reo; Sasaki, Shigeru; Sasaki, Yasushi; Mitsuya, Hiroaki; Nishikawa, Noriko; Yamaguchi, Koji; Hirata, Koichi; Itoh, Fumio; Tokino, Takashi; Mori, Mitsuru; Imai, Kohzoh; Shinomura, Yasuhisa

doi:10.1038/sj.onc.1210259

Cited by 204 publications

(198 citation statements)

References 38 publications

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“…Although it is well known that mutation in APC, CTNNB1 and AXIN is infrequent in GC, we found that the majority of GC cells showed activation and nuclear accumulation of b-catenin and methylation of multiple SFRP genes (Nojima et al, 2007). Among those GC cells, only a few cell lines in which APC or CTNNB1 was mutated showed significant upregulation of TCF/LEF transcriptional activity (Nojima et al, 2007).…”

Section: Genetics and Genomicsmentioning

confidence: 66%

“…We previously reported that three of the five SFRP genes (SFRP1, SFRP2 and SFRP5) were frequently methylated and silenced in CRC and GC cells (Suzuki et al, 2002;Nojima et al, 2007). For that reason, in the present study we initially evaluated the expression status of SFRP1, SFRP2 and SFRP5 in a panel of breast cancer cell lines.…”

Section: Analysis Of Wnt Antagonist Gene Expression In Breast Cancer mentioning

confidence: 98%

“…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.…”

Section: Genetics and Genomicsmentioning

confidence: 99%

“…Fluorescence-activated cell sorting (FACS) analysis was carried out as described previously (Nojima et al, 2007). Briefly, 2 Â 10 6 cells …”

Section: Flow Cytometrymentioning

confidence: 99%

“…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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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 Genomicsmentioning

confidence: 66%

Section: Analysis Of Wnt Antagonist Gene Expression In Breast Cancer mentioning

confidence: 98%

Section: Genetics and Genomicsmentioning

confidence: 99%

“…Fluorescence-activated cell sorting (FACS) analysis was carried out as described previously (Nojima et al, 2007). Briefly, 2 Â 10 6 cells …”

Section: Flow Cytometrymentioning

confidence: 99%

mentioning

confidence: 99%

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Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

et al. 2008

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MiR‐125b regulates SFRP5 expression to promote growth and activation of cardiac fibroblasts

Bie

Sun

Geng

et al. 2016

Cell Biology International

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Myocardial fibrosis (MF), which typically occurs after a myocardial infarction (MI), is a major factor involved in the process of ventricular remodeling and subsequent progression to heart failure. Current studies have found that various microRNAs (miRNAs), such as miR-125b, play an important role in this process. However, few studies have investigated the specific mechanism of miR-125b. Transfection of miR-125b mimics into cardiac fibroblasts (CFs) resulted in significantly increased expression of the myofibroblast marker alpha-smooth muscle actin (α-SMA) and vinculin by Western blot analysis, while transfection of miR-125b inhibitors resulted in the opposite effect. Analysis of putative CF target genes for miR-125b revealed that miR-125b specifically inhibits expression of secreted frizzled-related protein 5 (SFRP5). SFRP5 inhibited expression of α-SMA and collagen I and III in CFs, while miR-125b promoted the expression of these proteins. Cotransfection of the SFRP5 overexpression vector and miR-125b mimics did not result in significant upregulation of SFRP5 expression or downregulation of α-SMA and collagen I and III. Further analysis revealed that miR-125b promotes the proliferation and migration of CFs and inhibits their apoptosis, while SFRP5 exhibits the opposite effects. These results indicate that miR-125b can regulate SFRP5 expression and thus influence the growth and activation of CFs. Hence, this study provides important insight into possible approaches for the prevention and treatment of MF after an MI.

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Promoter methylation of the Wnt/β‐catenin signaling antagonist Dkk‐3 is associated with poor survival in gastric cancer

Tao

Cheng

et al. 2008

Cancer

122

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Objective Infliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion. Methods The percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, 1 hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, 1 hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured. Results There were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P < 0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation. Conclusion Our findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti–tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium.

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Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

Cited by 204 publications

References 38 publications

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

MiR‐125b regulates SFRP5 expression to promote growth and activation of cardiac fibroblasts

Promoter methylation of the Wnt/β‐catenin signaling antagonist Dkk‐3 is associated with poor survival in gastric cancer

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