DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving ...genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
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•TARID, a TCF21 antisense lncRNA, is downregulated in cancer cells•TARID binds to the TCF21 promoter and mediates transcriptional activation•TARID recruits GADD45A/TDG, thus promoting base excision-mediated demethylation•A lncRNA can serve as an address label for DNA demethylation
The function of most long noncoding RNAs (lncRNAs) is unknown. Arab et al. characterize TARID, a lncRNA that is antisense to the tumor suppressor TCF21, and find that it specifically directs demethylation and activation of TCF21 via GADD45A.
Prolactin and Risk of Epithelial Ovarian Cancer Hathaway, Cassandra A; Rice, Megan S; Townsend, Mary K ...
Cancer epidemiology, biomarkers & prevention,
09/2021, Letnik:
30, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ...ovarian cancer.
We conducted a pooled case-control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype.
Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (
= 0.045; OR, quartile 4 vs. 1 = 1.34; 95% CI = 0.97-1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR = 1.38; 95% CI = 0.74-2.58;
= 0.32 and OR = 1.41; 95% CI = 0.93-2.13;
= 0.08, respectively;
= 0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI ≥ 25 kg/m
, but not BMI < 25 kg/m
(corresponding OR = 2.68; 95% CI = 1.56-4.59;
< 0.01 and OR = 0.90; 95% CI = 0.58-1.40;
= 0.98, respectively;
< 0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis.
We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI ≥ 25 kg/m
.
This work supports a previous study linking higher prolactin with ovarian carcinogenesis in a high adiposity setting. Future work is needed to understand the mechanism underlying this association.
Evidence suggests that the hormonal milieu of pregnancy is an important determinant of subsequent cancer and other chronic diseases in both the mother and the offspring. Many of the existing ...maternity and birth cohorts include specimens drawn only once during pregnancy. How well a single blood specimen collected during a pregnancy characterizes exposure to these hormones throughout gestation, and also in subsequent pregnancies, is not well understood.
We used serial serum samples from 71 pregnant women (25 primiparous, 25 multiparous, and 21 with two consecutive pregnancies) with natural, complication-free pregnancies and a healthy offspring at term who participated in a population-based screening trial for congenital infections in Finland between January 1st, 1988 and June 30, 1989 and provided a blood sample in each trimester.
Hormone levels were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimester (e.g., estradiol, rT1 vs. T2 = 0.51 and rT2 vs. T3 = 0.60, p < 0.01; rT1 vs. T3 = 0.32, p < 0.05). Concentrations of sRANKL remained stable throughout gestation, whereas estradiol, estrone, progesterone, testosterone, prolactin, and osteoprotegerin increased throughout pregnancy. First trimester hormone concentrations explained less of the variation in the third trimester on their own than second trimester hormone levels (e.g. estradiol R(2) T1 = 16 % and R(2) T2 = 42 %). Addition of maternal (e.g., smoking) and/or child characteristics (e.g., sex) improved the accuracy of the 3rd trimester estimates for some of the hormones.
One hormone measurement in early pregnancy, in conjunction with maternal and fetal characteristics, permits estimation of 3rd trimester hormone concentrations. Therefore, single hormone measurements available from maternity cohorts are suitable to quantify hormone exposure during pregnancy. To our knowledge, we provide the first data on correlations between hormone concentrations both across trimesters of a single pregnancy, as well as between two subsequent pregnancies.
Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase ...(PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE: Chlamydia trachomatis (C. trachomatis) infection has been suggested to promote epithelial ovarian cancer (EOC) development. This study sought to explore the presence of C. trachomatis DNA ...and chlamydial heat shock protein 60 (chsp60) in ovarian tissue, as well as anti-chlamydial IgG antibodies in plasma, in relation to subtypes of EOC. METHODS: This cross-sectional cohort consisted of 69 women who underwent surgery due to suspected ovarian pathology. Ovarian tissue and corresponding blood samples were collected at the time of diagnosis. In ovarian tumor tissue, p53, p16, Ki67 and chsp60 were analyzed immunohistochemically, and PCR was used to detect C. trachomatis DNA. Plasma C. trachomatis IgG and cHSP60 IgG were analyzed with a commercial MIF-test and ELISA, respectively. RESULTS: Eight out of 69 women had C. trachomatis DNA in their ovarian tissue, all were invasive ovarian cancer cases (16.7% of invasive EOC). The prevalence of the chsp60 protein, C. trachomatis IgG and cHSP60 IgG in HGSC, compared to other ovarian tumors, was 56.0% vs. 37.2% P = .13, 15.4% vs. 9.3% P = .46 and 63.6% vs. 45.5% P = .33 respectively. None of the markers of C. trachomatis infection were associated with p53, p16 or Ki67. CONCLUSIONS: C. trachomatis was detected in invasive ovarian cancer, supporting a possible role in carcinogenesis of EOC. However, there were no statistically significant associations of chsp60 in ovarian tissue, or plasma anti-chlamydial IgG antibodies, with any of the subtypes of ovarian tumors.
BACKGROUND:Chlamydia trachomatis salpingitis causes inflammatory damage to the fallopian tube and could potentially cause initiation and progression of high-grade serous ovarian cancer (HGSC). ...Furthermore, C. trachomatis infection may stimulate mucin 1 (MUC1) protein production, possibly affecting anti-MUC1 antibody levels. The aim of this study was to examine if serology indicating past infection with C. trachomatis as well as anti-MUC1 production was associated with subsequent risk of HGSC. MATERIALS AND METHODS: In a prospective nested case–control study within the Northern Sweden Health and Disease Study and the Northern Sweden Maternity Cohort, the prevalence of chlamydial and anti-MUC1 antibodies was analyzed in blood samples drawn more than one year before diagnosis from 92 women with HGSC and 359 matched controls. Matching factors were age, date at blood draw, and sampling cohort. Plasma C. trachomatis IgG was analyzed using commercial micro-immunofluorescence test; chlamydial Heat Shock Protein 60 IgG (cHSP60) and anti-MUC1 IgG were analyzed with ELISA technique. RESULTS: The prevalence of C. trachomatis IgG and cHSP60 IgG antibodies, as well as the level of anti-MUC1 IgG was similar in women with HGSC and controls (16.3% vs. 17.0%, P = 0.87; 27.2% vs. 28.5%, P = 0.80; median 0.24 vs. 0.25, P = 0.70). Anti-MUC1 IgG and cHSP60 IgG levels were correlated (r = 0.169; P < 0.001). CONCLUSIONS: The findings of this prospective nested case–control study did not support an association between C. trachomatis infection, as measured by chlamydial serology, or anti-MUC1 IgG antibodies, and subsequent risk of HGSC.
Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes ...other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Endometrial cancer (EC) is the most common gynecologic malignancy in Sweden and it has various prognostic factors. The LRIG family is a group of three integral surface proteins with a similar domain ...organization. The study aimed to explore LRIG family as prognostic factor proteins in EC. The initial study cohort included 100 women with EC who were treated at the Department of Women's and Children's Health, Karolinska University Hospital Solna, between 2007 and 2012. We assessed the associations between LRIG protein expression and type, grade, and stage of EC, as well as progression-free and overall survival. Immunohistochemistry results revealed that most women in the analytical sample had >50% LRIG1-, LRIG2- and LRIG3-positive cells. A statistically significant association was observed between having a high number of LRIG3-positive cells and superior overall survival (incidence rate ratio = 0.977; 95% confidence interval: 0.958-0.996,
= 0.019). Moreover, positive LRIG3 staining of the cell membrane was associated with reducing in the risk of death (hazard ratio = 0.23; 95% confidence interval: 0.09-0.57). Our results show that LRIG3 expression might be a prognostic factor in EC. The role of LRIG1 and LRIG2 expression remains to be further investigated.
Although communications between mammalian oocytes and their surrounding granulosa cells mediated by the Kit–Kit ligand (KL, or stem cell factor, SCF) system have been proven to be crucial for ...follicular development, Kit downstream signaling pathways in mammalian oocytes are largely unknown. In this study, by using ovaries and isolated oocytes from postnatal mice and rats, we demonstrated for the first time that components of the PI3 kinase pathway, the serine/threonine kinase Akt (PKB) which enhances cellular proliferation and survival, and an Akt substrate FKHRL1 which is a transcription factor that leads to apoptosis and cell cycle arrest, are expressed in mammalian oocytes. By using an in vitro oocytes culture system, we found that oocytes-derived Akt and FKHRL1 are regulated by SCF. Treatment of cultured oocytes with SCF cannot only rapidly phosphorylate and activate Akt, but also simultaneously phosphorylate and may therefore functionally suppress FKHRL1, through the action of PI3 kinase. Together with our in situ hybridization and immunohistochemistry data that Akt and FKHRL1 are mostly expressed in oocytes in primordial and primary ovaries and reports that FKHRL1 gene-deficient mice exhibited excessive activation from primordial to primary follicles as well as enlarged oocyte sizes, we suppose that in mammalian oocytes, actions of granulosa cell derived SCF on primordial to primary follicle transition and subsequent follicle development may involve activation of Akt and inhibition of FKHRL1 activities in oocytes. The role of oocyte's Akt may be to enhance follicle development and the role of oocyte's FKHRL1 may be to inhibit follicle development. We propose that the cascade from granulosa cell SCF to oocyte Kit-PI3 kinase-Akt-FKHRL1 may play an important role to regulate the growth rate of mammalian oocytes and hypothetically also the oocyte secretion of factors that may regulate the activation and early development of ovarian follicles.
Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones.
We conducted a nested case-control study ...in the Northern Sweden Maternity Cohort (1975-2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression.
Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (OR
: 0.64 (0.41-1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (OR
: 1.57 (1.13-2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11-3.16)). None of the investigated hormones were associated with ER-/PR- disease, or with AR+ or AR+/ER+/PR+ disease.
Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.
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