Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma

Sogabe, Yohei; Suzuki, Hiromu; Toyota, Minoru; Ogi, Kazuhiro; Isobe, Takashi; Nojima, Masanori; Sasaki, Yasushi; Hiratsuka, Hiroyoshi; Takenaka, Takashi

doi:10.3892/ijo.32.6.1253

Cited by 40 publications

(67 citation statements)

References 20 publications

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“…Therefore, contrary to Sogabe et al (35) who observed that SFRP-1 together with SFRP-2 and SFRP-5 were methylated in OSCC, we have noted an opposite epigenetic behaviour for SFRP-1, because it was significantly demethylated in cancer (p<0.05).…”

Section: Discussioncontrasting

confidence: 99%

“…Sogabe et al (35), studied only SFRP class of WNT-pathway inhibitors, our research focused on the two known classes of receptor and non-receptor WNT inhibitors, showing that a panel of these genes may be useful in clinical practice separating normal oral epithelia from the cancerous ones if their DNAs were analysed by methylation specific PCR technique.…”

Section: Discussionmentioning

confidence: 99%

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WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

Caraglia¹

2010

Oncol Rep

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Abstract. Epigenetic DNA methylations plays an important role in oral carcinogenesis. The soluble frizzled receptor protein (SFRP) family together with WIF-1 and DKK-3 encodes antagonists of the WNT pathway. Silencing of these genes leads to constitutive WNT signalling. Because aberrant expression of ß-catenin might be associated with the epigenetic inactivation of WNT inhibitors, we analyzed, in a collection of primary OSCC with matched normal oral mucosa, the methylation status of a complete panel of genes, SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3, that are involved directly and indirectly in WNT pathway, in order to demonstrate WNT-pathway activation in the absence of ß-catenin and/or APC/Axin mutations during oral carcinogenesis. Methylation-specific PCR (MSP) was performed to study inactivation of SFRP-1, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 genes in 37 cases of paraffin embedded oral cancer. This study showed that the methylation is an important epigenetic alteration in oral cancer. In particular, SFRP-2, SFRP-4, SFRP-5, WIF-1, DKK-3 revealed methylation status of their promoter in OSCC, whereas SFRP-1 showed demethylation in cancer. Fisher's exact test revealed statistically significant results (p<0.05) for all genes. The Wald test confirmed the statistically significant association between SFRP2-4-5 gene methylation and OSCC (p<0.05). SFRP-1 was also characterized by a different statistically significant epigenetic behaviour, because of it was demethylated in cancer (p<0.05). Statistical regression test showed high levels of sensitivity, specificity and accuracy for SFRP genes, while WIF-1 and DKK-3 have reportedly high specificity, moderate accuracy but low sensitivity. This study suggests that a cause of catenin delocalization in oral cancer could be due to WNT pathway activation, by epigenetic alterations of SFRP, WIF-1 and DKK-3 genes.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

Caraglia¹

2010

Oncol Rep

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“…Veeck et al indicated that the promoter hypermethylation of SFRP1 gene was significantly associated with tumour stage, but not with lymph node status, and histologic type of invasive breast cancer [26]. However, the study of Sogabe showed that sFRP1,2,5 genes hypermethylation weren't connected with TNM classification and differentiation of tumors in oral squamous cell carcinoma [27]. Furthermore, Sato et al demonstrated that Dkk genes family were frequent targets of epigenetic silencing in gastric carcinoma and colorectal cancer, and found that the methylation status of each Dkk gene was not statistically significant with the tumor pT status, pN status, pM status and tumor stage [17].…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma

Guo

Guo²,

Chen³

et al. 2011

neo

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The canonical Wnt signalling pathway plays a key role during embryogenesis and pathogenesis of various types of tumors. Recently, several studies have shown that the promoter hypermethylation of Wnt-antagonist genes, including sFRP-1, , have been certified to contribute to the tumorigenesis of several cancers.The aim of this study was to investigate the promoter methylation of Wnt-antagonist genes in gastric cardia adenocarcinoma (GCA) and corresponding adjacent non-cancerous tissues, and to establish the possible relationship between DNA methylation status and the pathogenesis of GCA.MSP, RT-PCR methods were applied respectively to examine the CpG methylation of the Wnt-antagonist genes and its mRNA expression in tumors and corresponding non-cancerous tissues, and immunohistochemistry method was used to determine protein expression of β-catenin(the key factor of the Wnt signalling pathway) and cyclin D1(the target gene of this pathway).The frequency of promoter methylation of sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1 and Dkk-3 genes in GCA tumor tissues were 78.7%(74/94), 76.6%(72/94), 70.2%(66/94), 77.1%(73/94), 61.7%(58/94) and 21.3%(20/94), respectively, which were significantly higher than those in adjacent non-cancerous tissues. Furthermore, the frequencies of silenced mRNA expression of these six genes in GCA tumor tissues were significantly higher than those in adjacent non-cancerous tissues. Methylation levels of these six genes were all correlated with loss of mRNA expression. The ectopic expression of β-catenin and cyclin D1 was significantly more frequent in GCA tumor tissues than that in adjacent non-cancerous tissues and correlated with each Wnt-antagonist genes hypermethylation status.Epigenetic silencing of Wnt-antagonist genes expression by promoter hypermethylation may play an important role in gastric cardia adenocarcinoma.

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“…Recently, increasing numbers of TSGs associated with epigenetic alterations have been identified in RCCs, which imply that epigenetic regulation of TSGs may be an important mechanism for tumorigenesis in RCCs. Genes which have been found to be aberrantly methylated in RCCs at different frequencies include VHL, RASSF1A, p16, Timp-3, E-cadherin, b-catenin, SFRP1, SFRP2, SFRP4, SFRP5, DAL-1, COLIA1, KRT19, UCHL1, and UNC5C (9)(10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

The Tumor-Suppressive Function ofUNC5Dand Its Repressed Expression in Renal Cell Carcinoma

Lü

Dong

Zhou

et al. 2013

Clinical Cancer Research

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Purpose: As a newly added member of the UNC5H receptors, the function of UNC5D/H4 in tumorigenesis remains poorly defined. The aim of this study was to examine the expression of UNC5D in primary renal cell carcinomas (RCC), analyze the mechanisms responsible for its downregulation in RCC, and assess its functional relevance to tumor growth and migration.Experimental Design: Forty-four paired primary RCCs and corresponding adjacent noncancerous tissues were collected. The mRNA and protein expression level of UNC5D was assessed by reverse transcriptase-PCR, real-time PCR, or immunohistochemistry. Epigenetic alterations in UNC5D promoter and LOH in the UNC5D locus were also analyzed. Ectopic expression of UNC5D in renal cancer cells with silenced expression of UNC5D was used for analysis of the biologic functions of UNC5D.Results: UNC5D expression was attenuated in multiple carcinoma cell lines including renal cancer cells. Similar reduction was also observed in primary RCC tissues as compared with paired adjacent noncancerous tissues. Methylation-specific PCR showed hypermethylation in UNC5D promoter in a significant proportion (18 of 44) of tumor tissue (40.9%). LOH of UNC5D was observed in 13 of 44 patients with RCCs (29.5%). Restoration of UNC5D expression in renal cancer cells significantly inhibited cell proliferation, anchorage-dependent and -independent growth, as well as migration and invasion, whereas knockdown of UNC5D promoted cell growth. Furthermore, ectopic expression of UNC5D induced G 2 -M cell-cycle arrest.Conclusions: UNC5D is a functional tumor suppressor that is frequently downregulated in RCCs due to promoter hypermethylation and LOH.

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Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma

Cited by 40 publications

References 20 publications

WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

WNT pathway in oral cancer: Epigenetic inactivation of WNT-inhibitors

Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma

The Tumor-Suppressive Function ofUNC5Dand Its Repressed Expression in Renal Cell Carcinoma

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