HERV-K Hypomethylation in Ovarian Clear Cell Carcinoma Is Associated With a Poor Prognosis and Platinum Resistance

Iramaneerat, Kanokwan; Rattanatunyong, Prakasit; Khemapech, Nipon; Triratanachat, Surang; Mutirangura, Apiwat

doi:10.1097/igc.0b013e3182021c1a

Cited by 52 publications

(49 citation statements)

References 19 publications

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“…The reason why LINE-1 hypomethylation only was a prognostic marker of GC is unclear at present. However, a similar example can be seen in Iramaneerat et al's study 43 in which a close correlation was found between human endogenous retrovirus K (HERV-K) and LINE-1 methylation levels in ovarian clear cell carcinoma tissue samples but HERV-K methylation level only was closely associated with clinical outcome. These results indicate that despite close correlation between LINE-1 and ALU or HERV-K methylation levels, certain tissue types or phenotypes of cancer are associated with certain transposable elements and support the hypothesis that genomewide hypomethylation in cancer might be promoted by multiple mechanisms, including generalized and locus-specific.…”

Section: Discussionmentioning

confidence: 84%

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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Focal CpG island hypermethylation and diffuse genomic hypomethylation signify the changes in the DNA methylation status in cancer cells. ALU and LINE-1 repetitive DNA elements comprise~28% of the human genome. PCR-based measurements of these repetitive DNA elements can be used as a surrogate marker of the genomewide methylation content. Our study aimed to identify the timing of ALU and LINE-1 hypomethylations during multistep gastric carcinogenesis and their prognostic implications in gastric cancer (GC). In our study, we analyzed the methylation statuses of ALU and LINE-1 in 249 cases of gastric biopsy samples and another independent set of 198 cases of advanced GC by pyrosequencing. Regardless of the Helicobacter pylori infection status, a significant decrease in the ALU methylation levels was noted during the transitions from chronic gastritis to intestinal metaplasia and from gastric adenoma to GC. LINE-1 methylation decreased during the transition from intestinal metaplasia to gastric adenoma and no further decrease occurred during the transition from gastric adenoma to GC. A low LINE-1 methylation status was strongly associated with poor prognosis in GC. A multivariate analysis revealed that LINE-1 methylation status was an independent prognostic factor. Our findings suggest that ALU and LINE-1 hypomethylations are early events during multistep gastric carcinogenesis. Furthermore, the LINE-1 methylation status can be used as a molecular biomarker to define a subset of GC patients with poor prognosis.Focal promoter CpG island hypermethylation and generalized genomic hypomethylation signify the changes in the DNA methylation status in human cancer cells. Promoter CpG island hypermethylation is an important mechanism that inactivates tumor suppressor and tumor-related genes; meanwhile, generalized genomic hypomethylation contributes to genomic or chromosomal instability.1-3 Genomic hypomethylation mainly affects repetitive transposable DNA elements, which comprise 45% of the human genome 4 ; these elements reside mainly in the intergenic and intronic regions of the genome and in noncoding and coding exons of the genome to a much lesser extent.5 Long interspersed nucleotide element-1 (LINE-1) and ALU are major constituents of interspersed DNA repeats, constituting $17% and 11% of the human genome, respectively. 4CpG sites located within LINE-1 and ALU are usually methylated in normal somatic tissues, a mechanism that is believed to have evolved as a major defense mechanism to repress these transposable genetic elements.6 Demethylation of transposable elements is hypothesized to facilitate genomic instability by leading to retrotransposition of transposable elements, hypomethylated genome-associated error-prone repair of replication-independent endogenous double-strand breaks, and dysregulation of DNA repair genes. [7][8][9][10][11] In addition to bringing about genomic structural variation, demethylation of transposable element promoters dysregulates gene expression by upregulating the transcription of genes l...

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Section: Discussionmentioning

confidence: 84%

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Bae

Shin

Kwon

et al. 2012

Intl Journal of Cancer

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“…38,39 In turn, epigenomes can be also responsible for modulating the response to environmental factors. [40][41][42][43][44][45][46]47 In the modulation of microbiota colonization, we theorize that epigenetically regulated mechanisms may be responsible for differential immune responses, the establishment of more or less permeable epithelial barriers, and bacterial metabolite processing, which will favor the colonization of particular bacterial communities.…”

Section: Discussionmentioning

confidence: 99%

Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease

et al. 2016

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Preterm birth is the leading cause of infant morbidity and mortality. Necrotizing enterocolitis (NEC) is an inflammatory bowel disease affecting primarily premature infants, which can be lethal. Microbial intestinal colonization may alter epigenetic signatures of the immature gut establishing inflammatory and barrier properties predisposing to the development of NEC. We hypothesize that a crosstalk exists between the epigenome of the host and the initial intestinal colonizing microbiota at critical neonatal stages. By exposing immature enterocytes to probiotic and pathogenic bacteria, we showed over 200 regions of differential DNA modification, which were specific for each exposure. Reciprocally, using a mouse model of prenatal exposure to dexamethasone we demonstrated that antenatal treatment with glucocorticoids alters the epigenome of the host. We investigated the effects on the expression profiles of genes associated with inflammatory responses and intestinal barrier by qPCR-based gene expression array and verified the DNA modification changes in 5 candidate genes by quantitative methylation specific PCR (qMSP). Importantly, by 16S RNA sequencing-based phylogenetic analysis of intestinal bacteria in mice at 2 weeks of life, we showed that epigenome changes conditioned early microbiota colonization leading to differential bacterial colonization at different taxonomic levels. Our findings support a novel conceptual framework in which epigenetic changes induced by intrauterine influences affect early microbial colonization and intestinal development, which may alter disease susceptibility.

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“…Our finding of expression in ovarian somatic cells [11] together with decreased DNA methylation at L1 promoter region associated with the progression of cervical and uterus cancers [26] and poor prognosis in ovarian carcinomas [27] led us to investigate whether piRNA pathway genes could play a role in EOCs. In this study, we investigated the expression of PIWIL1 – 4 and MAEL in 25 EOC, 19 benign tumor samples, and 8 normal ovarian tissues.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of piRNA Pathway Genes in Epithelial Ovarian Cancer

et al. 2014

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The importance of the Piwi-interacting RNA (piRNA) pathway for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control raises possible roles of this pathway in cancer. Indeed aberrant expression of human PIWI orthologs and Maelstrom has been observed in various cancers. In this study we explored the expression and function of piRNA pathway genes in human ovarian cancer, based on our recent work, which showed widespread expression of piRNA pathway genes in the mammalian. Our work shows that PIWIL1 and MAEL expression is significantly increased in malignant EOC (n = 25) compared to benign tumor tissues (n = 19) and normal ovarian tissue (n = 8). The expression of PIWIL3 is lower in malignant and benign tissues when compared to normal ovary. Sequencing of PIWIL1 transcript revealed that in many tumors deletion of exon 17 leads to the introduction of a premature stop codon in the PIWI domain, likely due to a splicing error. In situ hybridization on tumor sections revealed that L1, PIWIL1, 2 and MAEL are specifically expressed in epithelial cells (cancerous cells) of EOC. Furthermore, PIWIL2 and MAEL are co-expressed in the stromal cells adjacent to tumor cells. Since PIWIL1 and MAEL are up regulated in malignant EOC and expressed in the epithelial cells, we investigated if these two genes affect invasiveness of ovarian cancer cell lines that do not normally express these genes. PIWIL1 and MAEL were transiently over expressed in the ovarian cancer cell line SKOV3, followed by real-time measurements of cell invasiveness. Surprisingly both PIWIL1 and MAEL over expression decreased the invasiveness of SKOV3 cells. Our findings support a growing body of evidence that shows that genes in this pathway are upregulated in cancer. In ovarian cancer we show for the first time that Piwil1 transcript may often be abnormal result in non functional product. In contrast to what has been observed in other cell types, we found that PIWIL1 and MAEL have a repressive effect on cell invasiveness.

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HERV-K Hypomethylation in Ovarian Clear Cell Carcinoma Is Associated With a Poor Prognosis and Platinum Resistance

Abstract: Methylation levels of HERV-K, HERV-E, and LINE-1 are decreased during OCCC multistep carcinogenesis. Moreover, HERV-K hypomethylation is a promising biomarker for predicting OCCC treatment response and prognosis.

Cited by 52 publications

References 19 publications

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

ALU and LINE‐1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications

Epigenome-Microbiome crosstalk: A potential new paradigm influencing neonatal susceptibility to disease

Overexpression of piRNA Pathway Genes in Epithelial Ovarian Cancer

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