Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma

Hanafusa, Tadashi; Yumoto, Yasuhiro; Nouso, Kazuhiro; Nakatsukasa, Harushige; Onishi, Toru; Fujikawa, Tatsuya; Taniyama, Mayumi; Nakamura, Shinichiro; Uemura, Masayuki; Takuma, Yoshitaka; Yumoto, Eiichiro; Higashi, Toshihiro; Tsuji, Takao

doi:10.1016/s0304-3835(01)00736-4

Cited by 116 publications

(93 citation statements)

References 30 publications

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“…18 We previously reported that the aberrant DNA methylation of IGFBP-3 was responsible for the loss of its expression in hepatocellular carcinomas (HCC). 19 In addition, Chang and colleagues reported that IGFBP-3 was frequently methylated and significantly associated with a poor prognosis in stage I nonsmall-cell lung cancer. 20,21 These facts suggest that IGFBP-3 acts as a TSG in several kinds of human cancers.…”

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confidence: 99%

“…19,22 In addition, a known polymorphism at the 2202 locus of IGFBP-3 that causes variations in IGFBP-3 expression is located within a p53 consensus sequence. These facts strongly support the hypothesis that the methylation status of the p53 consensus sequences in the promoter region is crucial to the regulation of IGFBP-3 expression and may be an appropriate target for examining the methylation status.…”

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confidence: 99%

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

Tomii

Tsukuda

Toyooka

et al. 2006

Intl Journal of Cancer

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Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p 5 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. ' 2006 Wiley-Liss, Inc.

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

Tomii

Tsukuda

Toyooka

et al. 2006

Intl Journal of Cancer

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“…(8) IGFBP-3 is the most abundant IGFBP that is present in non-cancerous liver tissues and serves as a negative regulator of cell proliferation in human HCC. (9)(10)(11)(12) IGFBP-3 is also known to regulate cell growth independently of its effects on IGFstimulated growth in other types of malignancy. (13)(14)(15)(16) In our present study, we investigated how IGFBP-3 exerts its antiproliferative effects on HCC cell lines in culture, and using immunohistochemical analyses we further examined whether or not the expression of IGFBP-3 in human clinical samples is associated with the clinicopathological characteristics of HCC.…”

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High expression of insulin‐like growth factor binding protein‐3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma

Aishima¹,

Basaki

Oda³

et al. 2006

Cancer Science

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H epatocellular carcinoma (HCC) is one of the most common and aggressive malignant tumors worldwide. The longterm prognosis of HCC patients has remained unsatisfactory due to the high incidence of intrahepatic recurrence, which depends on portal venous invasion and the high incidence of intrahepatic metastasis, as well as multicentric development of new tumors.(1,2) Moreover, our understanding of the molecular mechanisms underlying the progression of HCC and the development of effective therapeutic targets remain to be studied in further detail.One candidate among the many growth factors that are closely associated with growth of HCC cells is insulin-like growth factor (IGF).(3) The biological effects of IGF are mediated via type 1 IGF receptor (IGF-1R), which leads to activation of the mitogenactivated protein kinase (MAPK) signaling pathway involved in cell growth and metabolism.(4,5) Mutation of another type 2 receptor (M6P/IGF-2R) and upregulation of IGF-II are expected to be responsible for the early stages of human hepatocarcinogenesis. (6,7) However, it remains unclear how the IGF system is involved in the progression of HCC. IGF are known to bind to IGF binding proteins (IGFBP), which regulate activity and function of IGF. (8) IGFBP-3 is the most abundant IGFBP that is present in non-cancerous liver tissues and serves as a negative regulator of cell proliferation in human HCC.(9-12) IGFBP-3 is also known to regulate cell growth independently of its effects on IGFstimulated growth in other types of malignancy. (13)(14)(15)(16) In our present study, we investigated how IGFBP-3 exerts its antiproliferative effects on HCC cell lines in culture, and using immunohistochemical analyses we further examined whether or not the expression of IGFBP-3 in human clinical samples is associated with the clinicopathological characteristics of HCC. We discuss plausible roles of IGFBP-3 in the IGF-dependent and -independent cell proliferation of HCC, and also the clinical significance of IGFBP-3 in patients with HCC.

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“…Of the 15 tumours methylated at assay-B, all but one were also methylated at the upstream part of the island, which supports the theory that de novo hypermethylation may gradually propagate through an island during neoplastic progression, initiating from the outer flanks of the CpG island (Mummaneni et al, 1995;Graff et al, 1997). An interesting finding was that the majority of prostate cancers were unmethylated around a methylation hotspot (corresponding to the p-53, AP-2 and Sp-1/Sp3 binding sites), reported in both non-small cell lung carcinoma (61%) and hepatocellular carcinoma (33%) (Chang et al, 2002;Hanafusa et al, 2002). These results clearly show that methylation is not uniformly spread throughout the IGFBP3 CpG island and therefore, the choice of CpG sites for investigation is an important consideration.…”

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confidence: 99%

“…Promoter hypermethylation has been proposed as a mechanism responsible for transcriptional silencing of IGFBP3 in hepatocellular carcinoma (Hanafusa et al, 2002), non-small cell lung carcinoma (Chang et al, 2002) and very recently in cancers of the bladder and ovary (Christoph et al, 2006;Wiley et al, 2006). In this study, we performed an extensive analysis of the methylation pattern of IGFBP3 in benign, preinvasive and cancerous prostate tissues.…”

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In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

et al. 2007

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Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5 0 CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (Po0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score X7 (P ¼ 0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in earlystage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.

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Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma

Cited by 116 publications

References 30 publications

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

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

High expression of insulin‐like growth factor binding protein‐3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

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