Dataset Information

Increased Intragenic IGF2 Methylation is Associated with Repression of Insulator Activity and Elevated Expression in Serous Ovarian Carcinoma.

ABSTRACT: Overexpression of insulin-like growth factor-II (IGF2) is a prominent characteristic of many epithelial ovarian malignancies. IGF2 imprinting and transcription are regulated in part through DNA methylation, which in turn regulates binding of the insulator protein CTCF within the IGF2/H19 imprint center. We have shown that IGF2 overexpression in ovarian cancer is associated with hypermethylation of CTCF binding sites within the IGF2/H19 imprint center. The aim of this study was to investigate the methylation and binding capacity of a novel putative CTCF binding motif located intragenic to IGF2 and determine how this relates to IGF2 expression. Among 35 primary serous epithelial ovarian cancer specimens, methylation of two CpGs, including one within the core binding motif and another adjacent to this motif, was higher in the 18 cancers with elevated IGF2 expression versus 10 with low expression (average 68.2 versus 38.5%; p?92%; average 93.2%; N?=?16). We confirmed binding of CTCF to this region in ovarian cancer cells, as well as the paralog of CTCF, Brother Of the Regulator of Imprinted Sites (BORIS), which is frequently overexpressed in cancers. The unmethylated CTCF binding motif has insulator activity in cells that express CTCF or BORIS, but not in cells that express both CTCF and BORIS. These intragenic CpG dinucleotides therefore comprise a novel paternal germline imprint mark and are located in a binding motif for the insulator protein CTCF. Methylation of the CpG dinucleotides is positively correlated with IGF2 transcription, indicating that increased methylation represses insulator function. These combined results suggest that methylation and CTCF binding at this region play important roles in regulating the level of IGF2 transcription. Our data have revealed a novel epigenetic regulatory element within the IGF2/H19 imprinted domain that is highly relevant to aberrant IGF2 expression in ovarian malignancies.

SUBMITTER: Huang Z

PROVIDER: S-EPMC3662894 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Increased Intragenic IGF2 Methylation is Associated with Repression of Insulator Activity and Elevated Expression in Serous Ovarian Carcinoma.

Huang Zhiqing Z Murphy Susan K SK

Frontiers in oncology 20130524

Overexpression of insulin-like growth factor-II (IGF2) is a prominent characteristic of many epithelial ovarian malignancies. IGF2 imprinting and transcription are regulated in part through DNA methylation, which in turn regulates binding of the insulator protein CTCF within the IGF2/H19 imprint center. We have shown that IGF2 overexpression in ovarian cancer is associated with hypermethylation of CTCF binding sites within the IGF2/H19 imprint center. The aim of this study was to investigate the ...[more]

PMID: 23745176

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Project description:High grade serous ovarian carcinoma (HGSC) without identifiable serous tubal intraepithelial carcinoma (STIC) within the fallopian tube (FT) occurs in approximately 50% of patients. The objective of this study was to use a multisite tumor sampling approach to study HGSC with and without STIC. RNAseq analysis of HGSC samples collected from multiple sites e.g. ovary, FT and peritoneum, revealed moderate levels of intrapatient heterogeneity in gene expression that could influence molecular profiles. Mixed-model ANOVA analysis of gene expression in tumor samples from patients with multiple tumor sites (n = 13) and patients with a single site tumor sample (n = 11) to compare HGSC-STIC to HGSC-NOSTIC identified neurotensin (NTS) as significantly higher (> two-fold change, False Discovery Rate (FDR) < 0.10) in HGSC-STIC. This data was validated using publicly available RNA-Seq datasets. Concordance between higher NTS gene expression and NTS peptide levels in HGSC-STIC samples was demonstrated by immunohistochemistry. To determine the role of NTS in HGSC, five ovarian cancer (OvCa) cell lines were screened for expression of NTS and its receptors, NTSR1 and NTSR3. Increased expression of NTS and NSTR1 was observed in several of the OvCa cells, whereas the NTSR3 receptor was lower in all OvCa cells, compared to immortalized FT epithelial cells. Treatment with NTSR1 inhibitor (SR48692) decreased cell proliferation, but increased cell migration in OvCa cells. The effects of SR48692 were receptor mediated, since transient RNAi knockdown of NTSR1 mimicked the migratory effects and knockdown of NTSR3 mimicked the anti-proliferative effects. Further, knockdown of NTSR1 or NTSR3 was associated with acquisition of distinct morphological phenotypes, epithelial or mesenchymal, respectively. Taken together, our results reveal a difference in a biologically active pathway between HGSC with and without STIC. Furthermore, we identify neurotensin signaling as an important pathway involved in cell proliferation and epithelial-mesenchymal transition in HGSC-STIC which warrants further study as a potential therapeutic target. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Project description:The survival duration of elderly patients with epithelial ovarian carcinoma is shorter than that of their younger counterparts. This variation in survival duration is likely attributed to differences in the distribution of histological type or grade, International Federation of Gynecology and Obstetrics (FIGO) staging, and undertreatment, but this observation remains controversial. This study aimed to investigate the biological factors other than selection bias associated with the decreased survival of elderly patients with ovarian carcinoma.A total of 314 serous ovarian cancer (SOC) patients from Jiangsu Institute of Cancer Research (JICR, PRC) between 2002 and 2012 were retrospectively analyzed, and 774 cases from MD Anderson Cancer Center (MDACC, USA) between 1992 and 2012 were used for validation. The 8-hydroxy-2'-deoxyguanine (8-OHdG) concentration in leukocyte DNA was evaluated by using commercially available enzyme-linked immunosorbent assay kits, and tissue expression was assayed through immunohistochemistry. The associations between survival durations and covariates were assessed by using a Cox proportional hazards model and by conducting a log-rank test.Advanced age ? 65 years was correlated with high histological grade (p = 0.02), performance status (p = 0.03), primary treatment (p = 0.00), and suboptimal surgery outcome (p = 0.04) in SOC patients from JICR. Age, FIGO stage, histological grade, and optimal surgery were independently associated with the progression-free survival (PFS; p = 0.03, p = 0.03, p = 0.02, and p = 0.04, respectively) and overall survival (OS; p = 0.02, p = 0.04, p = 0.02, and p = 0.02, respectively) of the SOC patients from JICR. The 8-OHdG concentration in the leukocyte DNA was higher in the elderly patients than in the younger cases. The high 8-OHdG concentration in the leukocyte DNA indicated poorer median OS (30.0 months, confidence interval [CI]: 23.5-36.5 vs. 42.8 months, [CI] 38.3-47.2) and PFS (14.6 months, [CI] 11.9-17.2 vs. 18.9 months, [CI] 14.4-23.4) than those of their corresponding counterparts in the SOC patients who achieved a clinical complete response from primary treatment.Compared with younger cases, elderly patients with SOC were commonly characterized by high tumor grade, poor performance status, and undertreatment. High 8-OHdG concentration in leukocyte DNA was associated with advanced age and poor prognosis in SOC patients.

Dataset Information

Increased Intragenic IGF2 Methylation is Associated with Repression of Insulator Activity and Elevated Expression in Serous Ovarian Carcinoma.

Publications

Increased Intragenic IGF2 Methylation is Associated with Repression of Insulator Activity and Elevated Expression in Serous Ovarian Carcinoma.

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