Epigenetic silencing of WIF-1 in hepatocellular carcinomas

Deng, Yun; Yu, Bin; Cheng, Qianqian; Jin, Jie; You, Hyun Ju; Ke, Ronghu; Shen, Qiujin; Shu, Huiqun; Yao, Guiyang; Zhang, Z.; Qin, Wenxin

doi:10.1007/s00432-010-0763-5

Cited by 26 publications

(17 citation statements)

References 24 publications

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“…Aberrant methylation of promoter regions that silence gene transcription has been recognized as a mechanism for inactivating tumor suppressor genes in some cancers [31,32]. WIF-1 silencing due to promoter methylation has also been recognized to facilitate tumorigenesis in nasopharyngeal and lung cancer, hepatocellular carcinoma, and colorectal cancer [33][34][35][36][37]. Considering this, we speculate that promoter hypermethylation is the key factor to affect the function of WIF-1 in neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…As a key antagonistic gene in the Wnt/β-catenin signaling pathway, WIF-1 inhibits the upstream of Wnt/β-catenin signal transduction by binding to Wnt proteins [13]. Downregulation of WIF-1 expression has been detected in various adult cancers [16][17][18][19][20]. However, the expression and molecular function of WIF-1 remains unknown in pediatric cancer, especially in neuroblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…This prevents the activation of Wnt target genes including c-myc and cyclin D1 [14][15]. Downregulation of WIF-1 has been reported in many human malignancies [16][17][18][19][20][21]. However, the expression and functional significance of WIF-1 in neuroblastoma remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

et al. 2014

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Neuroblastoma is the most common extracranial solid tumor in childhood and is associated with serious morbidity and mortality. The effective treatment of neuroblastoma remains one of the major challenges in pediatric oncology. The Wnt signaling pathway has been shown to play a significant role in the pathogenesis of adult and pediatric tumors. WIF-1 has been identified as an important Wnt antagonist which inhibits Wnt/β-catenin signaling by directly binding to Wnt proteins. However, the expression and function of WIF-1 in neuroblastoma remains unknown. The present study showed that WIF-1 was downregulated with high level promoter methylation in neuroblastoma cells, and was significantly upregulated after exposure to demethylating agent. This finding suggests that downregulation of WIF-1 was associated with its promoter methylation in neuroblastoma. To further study the potential function of WIF-1 in neuroblastoma, we constructed a plasmid that over-expressed WIF-1 and transfected the plasmid into one neuroblastoma cell line SK-N-SH. We found that restoration of WIF-1 inhibited the growth and proliferation of neuroblastoma cells in vitro. Morever, Wnt/β-catenin signaling activity and target genes expression were reduced by WIF-1 restoration. These results provide support that WIF-1 is downregulated and functions as a tumor suppressor by antagonizing Wnt/β-catenin signaling in neuroblastoma, suggesting a potential role as a therapeutic target in neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

et al. 2014

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“…for WIF-1 loss during hepatocarcinogenesis (72). Inactivity of the negative Wnt regulators Dkk2 and Dkk3 has been reported in human gastrointestinal tumours (73).…”

Section: Wnt/β-catenin Signalling and Cancermentioning

confidence: 99%

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

Shirolkar¹,

Pasic²,

Gogoi-Tiwari³

et al. 2018

jrenhep

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Chronic liver diseases (CLDs) are increasing in prevalence and their end-stage complications, namely, cirrhosis, liver failure and hepatocellular carcinoma represent major global challenges. The most common initiators of progressive CLD are viral hepatitis and long-term alcohol abuse as well as steatosis and steatohepatitis. Irrespective of the underlying aetiology, a common feature of CLD is the formation of hepatic ductular reactions, involving the proliferation of liver progenitor cells (LPCs) and their signalling to fibrosis-driving hepatic stellate cells. The Wnt/β-catenin pathway has been found to regulate development, stemness and differentiation, and alterations in its activity have been associated with tumour development. Recent data highlight the role of Wnt/β-catenin signalling in hepatic metabolism, steatosis and cancer, and suggest targeting of this pathway as a promising molecular strategy to potentially inhibit CLD progression and hepatocarcinogenesis.

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“…Although it remains possible that a functional sequence polymorphism exists outside the flanking regions analyzed, a more likely scenario is that SV235 carries an epiallele within its noncoding cly1 sequence, which has the effect of alleviating the repression of cly1 transcription. Such epialleles within transcriptional regulatory regions have been repeatedly associated with gene silencing in both plant and mammalian genomes (Shibuya et al 2006;Kinoshita et al 2007;Deng et al 2010;Ecker 2013). In rice, a genome-wide scan of DNA methylation has indicated that CpG methylation is rarest within regions stretching from slightly upstream to some 500 nt downstream of the transcriptional start site (Zemach et al A Novel Epiallele of cly1 in Barley 101 2010).…”

Section: Dna Methylation Within Cly1b2 Represses Transcriptionmentioning

confidence: 99%

An Epiallele at cly1 Affects the Expression of Floret Closing (Cleistogamy) in Barley

Wang

Ning

et al. 2014

Genetics

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The swelling of the lodicule is responsible for floret opening in many grass species, allowing for pollen dispersal and crosspollination. In barley, the closed floret habit (cleistogamy) is under the control of cly1, a gene that operates by inhibiting the development of the lodicule. In non-cleistogamous cultivars, cly1 mRNA is degraded by miR172-directed cleavage, allowing the lodicules to swell; however, in cultivars carrying the recessive allele cly1.b, a single-nucleotide substitution destroys the miR172 target site preventing mRNA cleavage. Barley cv. SV235 is cleistogamous; its cly1 coding sequence is identical to that of cly1.b, but its lodicules do develop, although insufficiently to produce a non-cleistogamous flower. In this cultivar, the downregulation of cly1 is unrelated to miR172-directed mRNA degradation, but rather is caused by an epiallele that represses transcription. Allelic relationships between known cly1 alleles were explored by the quantification of lodicule vascularization and an assessment of the response of the spike to the supply of exogenous auxin. The SV235 phenotype can be manipulated by a pre-anthesis application of 2,4-D, a feature that could be of interest in the context of hybrid barley grain production based on cleistogamy.T HE swelling of the lodicule, a structure found in the floret of many grass species and functionally related to the petal in the hermaphroditic angiosperm flower, drives apart the palea and lemma, thereby opening the floret so that it can release its pollen and be readily cross-pollinated (Briggs 1978). In barley, closed flowering (cleistogamous) variants are known. In some of these, the lodicule fails to swell (Kurauchi et al. 1994;Turuspekov et al. 2004;Honda et al. 2005;Wang et al. 2013). The cleistogamy 1 gene (cly1) has been shown to encode an AP2-protein and is a paralog of HvAP2-like in barley and Q in bread wheat (Simons et al. 2006;Nair et al. 2010;Simonov and Pshenichnikova 2012;Ning et al. 2013). In noncleistogamous barleys, cly1 mRNA is cleaved by an miRNA, with the result that the abundance of full-length gene product remains at a low level. Two cleistogamy alleles are known, cly1.b and cly1.c; in both cases, cly1 mRNA is not cleaved by miR172, resulting in the failure of the lodicule to swell. Exceptionally, in cv. SV235, although its cly1 coding sequence is identical to that of cly1.b, its lodicules do swell at anthesis, although insufficiently to force open the floret. Here, we show the genetic and epigenetic basis of the unusual lodicule development seen in cv. SV235. Materials and Methods Plant materialsGrain of the barley cultivars SV002 (OUA008, "Sanalta"), SV223 (OUU059, "Tammi"), SV230 (OUU305, "Badajoy"), SV235 (OUU326, "France 1"), SV237 (OUU329, "Cygne"), SV241 (OUU351, "Plumage"), SV242 (OUU352, "Imperial"), and SV255 (OUU613, "Otello"), along with the Hordeum vulgare subsp. spontaneum accession OUH602 (the OU numbers relate to the Barley and Wild Plant Resource Center collection, http://www.rib.okayama-u.ac.jp/barley/index...

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Epigenetic silencing of WIF-1 in hepatocellular carcinomas

Abstract: WIF-1 silencing as a result of its promoter hypermethylation may be a frequent event in HCC.

Cited by 26 publications

References 24 publications

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

Wnt inhibitory factor-1 functions as a tumor suppressor through modulating Wnt/β-catenin signaling in neuroblastoma

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

An Epiallele at cly1 Affects the Expression of Floret Closing (Cleistogamy) in Barley

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