Aberrant promoter methylation of <i>insulin‐like growth factor binding protein‐3</i> gene in human cancers

Tomii, Kunitoshi; Tsukuda, Kazunori; Toyooka, Shinichi; Dote, Hideaki; Hanafusa, Tadashi; Asano, Hiroaki; Naitou, Minoru; Doihara, Hiroyoshi; Kisimoto, Takumi; Katayama, Hideki; Pass, Harvey I.; Date, Hiroshi; Shimizu, Nobuyoshi

doi:10.1002/ijc.22341

Cited by 69 publications

(68 citation statements)

References 42 publications

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“…Both of these genes inhibit activation of the Wnt-signaling pathway by preventing the binding of Wnt ligands to the frizzled transmembrane receptors. The frequency of WIF-1 methylation in mesothelioma tissues was similar to that reported in previous studies (13,15,29) and its frequency is higher in mesothelioma compared to that of other genes, such as p16 (11.4%), RASSF1A (20.2%) and IGFBP-3 (32%) (8,9,20). This result suggests that WIF-1 methylation might play an important role in mesothelioma.…”

Section: Discussionsupporting

confidence: 88%

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Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma

Kohno

Amatya²,

Takeshima³

et al. 2010

Oncol Rep

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Abstract. 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 ß-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 ß-catenin suggesting no alteration of canonical Wnt signaling pathway. Our data suggest that WIF-1 promoter methylation is a common event in mesothelioma.

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Section: Discussionsupporting

confidence: 88%

“…RASSF1A, ESR1, IGFBP3, APC, CCND2, HPPBP1, BMP3b and BMP6 have been reported to be down-regulated by promoter methylation in mesothelioma. It has been suggested that these types of epigenetic changes contribute to tumorigenesis in mesothelioma (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma

Kohno

Amatya²,

Takeshima³

et al. 2010

Oncol Rep

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“…Characteristics of HOPX-b promoter methylation as compared with those of other genes associated with a high frequency of promoter methylation CDH4 (95%) (Miotto et al, 2004), Integrina4 (85%) (Park et al, 2004), KLF4 (80%) (Wei et al, 2005), Reprimo (79%) (Takahashi et al, 2005), Runx3 (45-71%) (Waki et al, 2003;Oshimo et al, 2004a), PGP9.5 (50-73%) (Yamashita et al, 2006;Tokumaru et al, 2008), RIZ1 (37-69%) (Tokumaru et al, 2003;Oshimo et al, 2004b), XAF1 (69%) (Zou et al, 2006), IGFBP3 (67%) (Tomii et al, 2007) and NMDAR2B (61%) (Liu et al, 2007) were the top 10 genes reported to have the highest frequencies of methylation in gastric cancer. We examined whether the frequency of HOPX-b methylation was comparable with those reported for such genes and whether HOPX-b methylation was a cancer-specific event in nine gastric cancer cell lines and the preliminary data set of 10 matched pairs (Supplementary Table 1) by bisulfite sequencing analysis (Figure 1b and Supplementary Figure 1).…”

Section: Hopx-b Promoter Structurementioning

confidence: 99%

Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer

et al. 2010

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HOP homeobox (HOPX) is an unusual homeobox gene encoding three spliced transcript variants, among which the only HOPX-b promoter harbors CpG islands. The characteristics of its promoter methylation was analyzed using bisulfite sequencing and quantitative-methylationspecific polymerase chain reaction (Q-MSP), and the effects of HOPX expression were also examined. HOPX-b expression was silenced in all gastric cancer cell lines tested; its expression could be restored by treatment with demethylating agent. On Q-MSP, HOPX-b hypermethylation (cut-off value of 3.55) was found in 84% (67 out of 80) of primary tumor tissues and 10% (8 out of 80) of the corresponding normal tissues and could discriminate normal from tumor tissues (Po0.0001). The prognosis of the advanced cases with HOPX-b hypermethylation was as poor as those with stage IV disease when cut-off value was set at 11.28. This finding was validated in an independent cohort of 90 advanced gastric cancers. The HOPX-b hypermethylation was also an independent prognostic factor (P ¼ 0.029) on multivariate analysis. Exogenous HOPX expression significantly inhibited cell proliferation, colony formation and invasion as well as enhanced apoptosis. Taken together, HOPX-b promoter methylation is a frequent and cancer-specific event in gastric cancer. Quantitative assessment of HOPX-b methylation has great clinical potential as a marker of tumor aggressiveness.

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“…IGFBP-3 has anti-proliferative, as well as, pro-apoptotic effects and suppression of IGFBP-3 has been implicated in the progression of several other tumors. 27 Also decreased were levels of transcripts for vascular endothelial growth factor (VEGF) receptor-1 (FLT1 or VEGFR1) (Ϫ22.7-fold), which interacts with VEGF-A, -B, and-E, as well as placental growth factor. Of relevance, low levels of VEGFR1 have been found in infantile hemangioma caused by mutations in the genes encoding VEGFR2 and TEM8.…”

Section: Endothelial-pericyte Signaling Systems In Proliferating Hemamentioning

confidence: 99%

Identification of Signaling Systems in Proliferating and Involuting Phase Infantile Hemangiomas by Genome-Wide Transcriptional Profiling

Calicchio

Collins

Kozakewich

2009

The American Journal of Pathology

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Infantile hemangiomas are characterized by rapid capillary growth during the first year of life followed by involution during early childhood. The natural history of these lesions creates a unique opportunity to study the changes in gene expression that occur in the vessels of these tumors as they proliferate and regress. Here we use laser capture microdissection and genome-wide transcriptional profiling of vessels from proliferating and involuting hemangiomas to identify differentially expressed genes. Relative to normal placental vessels, proliferating hemangiomas were characterized by increased expression of genes involved in endothelial-pericyte interactions, such as angiopoietin-2 (ANGPT2), jagged-1 (JAG1), and notch-4 (NOTCH4), as well as genes involved in neural and vascular patterning, such as neuropilin-2 (NETO2), a plexin domain containing receptor (plexinC1), and an ephrin receptor (EPHB3). Insulin-like growth factor binding protein-3 (IGFBP3) was down-regulated in proliferating hemangiomas. Involuting hemangiomas were characterized by the expression of chronic inflammatory mediators, such as the chemokine, stromal cellderived factor-1 (SDF-1), and factors that may attenuate the angiogenic response, such as a member of the Down syndrome critical region (DSCR) family. The identification of genes differentially expressed in proliferating and involuting hemangiomas in vivo will contribute to our understanding of this vascular lesion, which remains a leading cause of morbidity in newborn children.

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Aberrant promoter methylation of insulin‐like growth factor binding protein‐3 gene in human cancers

Cited by 69 publications

References 42 publications

Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma

Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma

Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer

Identification of Signaling Systems in Proliferating and Involuting Phase Infantile Hemangiomas by Genome-Wide Transcriptional Profiling

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