Aberrant hypermethylation of the FGFR2 gene in human gastric cancer cell lines

ArticleinBiochemical and Biophysical Research Communications 357(4):1011-5 · July 2007with22 Reads
DOI: 10.1016/j.bbrc.2007.04.051 · Source: PubMed
Abstract
We have previously shown that fibroblast growth factor receptor 2 (FGFR2) plays an important role in gastric carcinogenesis. In this study, we assessed DNA methylation status in the promoter region of FGFR2 gene in gastric cancer cell lines, and indicated that this region was highly methylated, compared with FGFR2-expressing gastric cancer cell lines. Moreover, the restoration of FGFR2 expression by treating methylated cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine strongly suggests that the loss of FGFR2 expression may be due to the aberrant hypermethylation in the promoter region of the FGFR2 gene. Thus, our results suggest that the epigenetic silencing of FGFR2 through DNA methylation in gastric cancer may contribute to tumor progression.
    • "FGFR2-amplified GC cell lines have high expression of FGFR2 protein or FGFR2 mRNA [32, 38]. On the other hand, the promoter region of FGFR2 gene is highly methylated, and FGFR2 mRNA expression is markedly reduced in several GC cell lines (SNU-1, SNU-5, SNU-484, and SNU-638) [39]. FGFR2 mRNA expression was restorable by demethylation using 5-aza-2 í® í° -deoxycytidine in cell lines with methylation of the promoter region of FGFR2, suggesting that aberrant hypermethylation of FGFR2 gene might lead to loss of FGFR2 expression. "
    [Show abstract] [Hide abstract] ABSTRACT: Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 (HER2) have become standard therapy for HER2-positive GC. An inhibitor of vascular endothelial growth factor receptor 2 or MET has also produced promising results in patients with GC. Fibroblast growth factor receptors (FGFR) play key roles in tumor growth via activated signaling pathways in GC. Genomic amplification of FGFR2 leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical relevance of FGFR in GC and examines FGFR as a potential therapeutic target in patients with GC. Preclinical studies in animal models suggest that multitargeted tyrosine kinase inhibitors (TKIs), including FGFR inhibitor, suppress tumor cell proliferation and delay tumor progression. Several TKIs are now being evaluated in clinical trials as treatment for metastatic or unresectable GC harboring FGFR2 amplification.
    Full-text · Article · May 2015
    • "Overexpression of FGFR1 is commonly observed in diverse cancer cells, and this phenomenon has been indicated to arise from hypomethylation of CpG islands within the promoter region (Goldstein et al., 2007). FGFR2 has been shown to be silenced by promoter methylation in a number of cancers, including thyroid cancer, pituitary neoplasia, gastric cancer, and breast cancer, probably due to the need for tumors to avoid FGFR2's previously mentioned tumor-suppressive effect (Kondo et al., 2007a,b; Park et al., 2007; Zhu et al., 2007 Zhu et al., , 2010a). FGFR3 has also been found to be methylated in lung cancer but is expressed with a much lower methylation status in squamous cell carcinomas (Cortese et al., 2008), suggesting that FGFR3 may play different roles in different tumors. "
    [Show abstract] [Hide abstract] ABSTRACT: Fibroblast growth factor receptors (FGFRs), encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) are tightly associated with many biological processes such as organ development, cell proliferation and migration. Studies over the past decades have validated the pivotal roles FGFRs play in tumorigenesis due to the regulation of diverse tumorigenesis-related processes, including cell survival, proliferation, inflammation, metastasis and angiogenesis. Interestingly, FGFR mutations in somatic cells leading to tumorigenesis and those in germ cells leading to developmental disorders are identical, suggesting that FGFR mutations result in different diseases due to their spatio-temporal expression. Thus, discoveries in developmental biology may also be applicable to cancer. FGFRs regulate the expression and/or the activity of a myriad of molecules (e.g. matrix metalloproteinases (MMPs) and Snail) that are tightly linked to tumorigenesis by four main signaling pathways (RAS-MAPK, PI3K-AKT, PLCγ-PIP2, and STAT), as well as other minor branches. Epigenetic and genetic alteration of FGFR genes, including DNA methylation, histone remodeling, microRNA regulation, single nucleotide polymorphisms (SNPs), gene missense mutations, amplification, and fusion of FGFRs with other genes, which result in gain or loss of FGFR function, have been identified in many types of cancer. In this review, we focus in particular on recent advances in the relationship between FGFR disorders and tumorigenesis.
    Full-text · Article · Jul 2014
    • "FGFR2 has been identified as a risk factor in breast cancer by association studies [30,353637. Two Genetic instability caused by loss of MSH3 in cancers [44] PCGF2 Polycomb group ring finger 2, involved in protein-protein interaction and transcription repression Tumor suppressor function [45] PDGFRL Platelet-derived growth factor receptor-like, a cell surface tyrosine kinase receptor Mutation and gene loss correlated with breast cancer progression [46] and prostate cancer [47] BCR Breakpoint cluster region Putative tumor suppressor in meningiomas [48] ASE genes DSC3 Desmocollin 3, a cell adhesion molecule in cadherin family Epigenetic silencing of DSC3 is a common event in breast cancer [49] FGFR2 Fibroblast growth factor receptor 2, a transmembrane tyrosine kinase Hypermethylation of FGFR2 found in gastric cancer [50] MYEOV Myeloma overexpressed, a putative transforming gene Epigenetically inactivated in esophageal squamous cell carcinomas [51] TNFRSF10D Tumor necrosis factor receptor superfamily, member 10 d, a member of TNF-receptor superfamily Aberrant methylation in multiple tumor type and mapped to tumor suppressor region in prostate cancer [52,53] MGMT O-6-methylguanine-DNA methyltransferase, a DNA repair gene Methylation of MGMT in many types of cancers [41,42,54] and associated with poorer overall and disease-free survival [55] LOH, loss of heterozygosity; ASE, allele-specific expression. intronic SNVs in FGFR2 have been reported to increase susceptibility to breast cancer by regulating the downstream gene expression level [35]. "
    [Show abstract] [Hide abstract] ABSTRACT: To identify potential tumor suppressor genes, genome-wide data from exome and transcriptome sequencing were combined to search for genes with loss of heterozygosity and allele-specific expression. The analysis was conducted on the breast cancer cell line HCC1954, and a lymphoblast cell line from the same individual, HCC1954BL. By comparing exome sequences from the two cell lines, we identified loss of heterozygosity events at 403 genes in HCC1954 and at one gene in HCC1954BL. The combination of exome and transcriptome sequence data also revealed 86 and 50 genes with allele specific expression events in HCC1954 and HCC1954BL, which comprise 5.4% and 2.6% of genes surveyed, respectively. Many of these genes identified by loss of heterozygosity and allele-specific expression are known or putative tumor suppressor genes, such as BRCA1, MSH3 and SETX, which participate in DNA repair pathways. Our results demonstrate that the combined application of high throughput sequencing to exome and allele-specific transcriptome analysis can reveal genes with known tumor suppressor characteristics, and a shortlist of novel candidates for the study of tumor suppressor activities.
    Full-text · Article · Nov 2010
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