Promoter methylation analysis of WNT/β-catenin pathway regulators and its association with expression of DNMT1 enzyme in colorectal cancer

Samaei, Nader Mansour; Yazdani, Yaghoub; Alizadeh‐Navaei, Reza; Azadeh, Hossein; Farazmandfar, Touraj

doi:10.1186/s12929-014-0073-3

Cited by 37 publications

(30 citation statements)

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“…The most known WNT pathway alterations, such as APC and AXIN2 inactivation by mutations or loss of heterozygosity, affect the APC-GSK3-Axin complex leading to b-catenin stabilization, thereby resulting in the constitutive activation of canonical WNT signaling in CRC. 10 Promoter hypermethylation of negative regulators of canonical WNT pathway like secreted frizzledrelated proteins (SFRPs), [11][12][13][14][15][16][17][18] dickkopf family proteins (DKKs), 11,17,[19][20][21] and WIF1 WNT inhibitory factor 11,17,21 has also been described in malignancies, including CRC. Methylation patterns of CRC and normal adjacent tissue samples were compared in most of the previous global methylation studies focusing on WNT signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2 0 -deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, b-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

et al. 2016

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“…21,22 Wnt pathway regulators are methylated in colorectal cancer cells with increased DNMT1 expression. 23 Epigenetic changes play a significant role in alteration of homeostasis of the epithelium, characterized by markedly enhanced proliferation, and development of cancer in normal adjacent tissue areas which are morphologically normal. 24 Secreted frizzled-related protein 1 (SFRP1) mRNA expression in normal adjacent tissue samples was higher than that from colorectal cancer samples.…”

Section: Wnt Signalingmentioning

confidence: 99%

Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers

Farooqı¹,

Tang²,

Li³

et al. 2015

IJN

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Research concerning the epigenome over the years has systematically and sequentially shown substantial development and we have moved from global inhibition of modifications of the epigenome toward identification and targeted therapy against tumor-specific epigenetic mechanisms. In accordance with this approach, several drugs with epigenetically modulating activity have received considerable attention and appreciation, and recently emerging scientific evidence is uncovering details of their mode of action. High-throughput technologies have considerably improved our existing understanding of tumor suppressors, oncogenes, and signaling pathways that are key drivers of cancer. In this review, we summarize the general epigenetic mechanisms in cancer, including: the post-translational modification of DNA methyltransferase and its mediated inactivation of Ras association domain family 1 isoform A, Sonic hedgehog signaling, Wnt signaling, Notch signaling, transforming growth factor signaling, and natural products with epigenetic modification ability. Moreover, we introduce the importance of nanomedicine for delivery of natural products with modulating ability to epigenetic machinery in cancer cells. Such in-depth and comprehensive knowledge regarding epigenetic dysregulation will be helpful in the upcoming era of molecular genomic pathology for both detection and treatment of cancer. Epigenetic information will also be helpful when nanotherapy is used for epigenetic modification.

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“…This signaling pathway is well known to be involved in the embryogenesis and carcinogenesis process (11). Also recognized as GPR49, LGR5 is a member of the G protein-coupled receptors, the largest family of cell-surface molecules involved in a signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Comparison of leucine-rich repeat-containing G protein-coupled receptor 5 expression in different cancer and normal cell lines

et al. 2016

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Abstract. Evaluating the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) may be useful for predicting the best models and achieving more accurate results in cancer research. Therefore, the aim of the present study was to analyze the LGR5 expression levels in different cell lines. Eight commonly used cell lines were assessed (COS-7, NIH3T3, HEK293, VERO, HeLa, BHK, HepG2 and AGS). All the cell lines were cultured in RPMI-1640 medium contain 10% fetal calf serum at 37˚C in humidified conditions with 5% CO 2 . According to the western blotting results, LGR5 was expressed in all cell lines. Densitometry results of LGR5 expression in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines. The results indicate that for the normal and cancer cell lines, BNK and AGS may be a better choice, respectively, for in vitro cancer studies. IntroductionCancer has become the major cause of mortality in certain countries in the 21st century (1). There are three models for cancer heterogeneity. Tumor heterogeneity is attained through genetic or epigenetic modifications. The stochastic model, as the first model, indicates that all tumor cells potentially are capable of self-renewal or differentiation, and are tumorigenic (2). In the second model, the hierarchical model, which is also known as the cancer stem cell (CSC) model of tumor growth, the ability of self-renew is considered for only a subset of tumor cells; the CSCs. These cells generate committed progenitor cells with limited proliferative potential, which ultimately lead to terminal differentiation (3-5). The third model is known as the complex model and this model suggests that epigenetic changes can potentially influence the tumor cell phenotype and function due to micro-environmental factors, thereby influencing tumor heterogeneity (2).Recently, a new CSC theory, known as tumor stem cells or tumor-initiating cells, has emerged. A CSC was precisely defined by the American Association for Cancer Research in 2006 as a cell within a tumor that has positive susceptibility to self-renew and to reason the heterogeneous progeny of cancer cells that are contained within the tumor (6). The CSC model was previously described for hematological malignancies in 1997 (7).Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is considered an intestinal stem cell marker (8).LGR5 has a transducer role in the Wnt signaling pathway (9,10). This signaling pathway is well known to be involved in the embryogenesis and carcinogenesis process (11). Also recognized as GPR49, LGR5 is a member of the G protein-coupled receptors, the largest family of cell-surface molecules involved in a signaling pathway. The size of the LGR5 gene is ~144 kb and it is located at position 12q22-q23 of chromosome 12. The LGR5 protein has seven transmembrane domains. Experimental findings showed that this protein in the mature form contains <17 leucine-rich repeats, each comp...

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Promoter methylation analysis of WNT/β-catenin pathway regulators and its association with expression of DNMT1 enzyme in colorectal cancer

Cited by 37 publications

References 24 publications

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers

Comparison of leucine-rich repeat-containing G protein-coupled receptor 5 expression in different cancer and normal cell lines

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