Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adiponectin is a hormone secreted exclusively by adipocytes, and obesity is an established risk factor for endometrial cancer. We have, thus, evaluated the association of adiponectin with the occurrence of endometrial cancer. Questionnaire information and blood samples were taken before treatment from 84 women with newly diagnosed, histologically confirmed endometrial cancer and 84 control women who were admitted for minor gynecologic problems, mainly pelvic prolapse. Adiponectin levels were measured by immunoassay. The results were analyzed through multiple logistic regression and controlled for known risk factors for endometrial cancer, leptin, as well as major components of the IGF system (IGF-I, IGF-II, and IGF-binding protein 3). Among control women, there was no significant association of adiponectin with age or parity. Although there was no association of adiponectin with endometrial cancer among women 65 yr or older, there was an inverse, fairly strong, and statistically significant inverse association among younger women. Among women younger than 65 yr, an increase of adiponectin by 1 SD was associated with a more than 50% reduction of the risk for endometrial cancer [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.24-0.81], even after controlling for body mass index and other potential confounders. Among all women, the adjusted OR for a 1 SD increase in adiponectin was not significant (OR, 0.78; 95% CI, 0.56-1.10) but was significant for a one quintile increase in adiponectin (OR, 0.74; 95% CI, 0.56-0.97). In women younger than 65 yr, among whom obesity represents a powerful risk factor for endometrial cancer, adiponectin is inversely and significantly related to the risk of this disease. This association is independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known endometrial cancer risk factors. Future studies are needed to prove causality and provide insight on both the mechanism of action of this hormone and its potential role in endometrial cancer.
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PMID:Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. 1262 74

Adiponectin, an adipocyte-secreted hormone, is closely and inversely associated with insulin resistance and was recently found to be inversely and independently associated with endometrial cancer. Because insulin resistance in the setting of obesity has also been associated with the development of breast cancer, we have hypothesized that decreased adiponectin levels might underlie the association between breast cancer and obesity/insulin resistance. We evaluated the association of adiponectin with the occurrence of breast cancer in a case-control study comprising 174 women with newly diagnosed, histologically confirmed breast cancer and 167 controls. We found an inverse, fairly strong, and statistically significant association of serum adiponectin with breast cancer (odds ratio, 0.84; 95% confidence interval, 0.71-0.99). Importantly, despite a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women (odds ratio, 0.82; 95% confidence interval, 0.67-1.00), no such significant association between adiponectin and breast cancer was found among premenopausal women. The observed associations were independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known risk factors for breast cancer. Future studies are needed to prove causality and provide further insights into both the mechanisms underlying the actions of this hormone and its potential role in breast cancer.
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PMID:Adiponectin and breast cancer risk. 1500 94

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a mitogenic agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.
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PMID:Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways. 1672 88

Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.
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PMID:Role of neuropeptides in appetite regulation and obesity--a review. 1693 29

Menstrual irregularity is a common occurrence during adolescence, especially within the first 2-3 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. Estrogen-deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen-replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities.
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PMID:The pathophysiology of amenorrhea in the adolescent. 1857 22

Signal transducer and activator of transcription (STAT3) maintained invasiveness of endometrial cancer cell line. STAT3 mediated signaling for oncogenic growth stimulated by leptin (Ob) and hypoxia-inducible factor 1 (HIF-1). Therefore, we studied STAT3 in relation with HIF-1alpha, Ob, leptin receptor (ObR) and clinical and pathological variables with immunohistochemistry in 48 human endometrioid adenocarcinomas. Nuclear location was a proof of activity of STAT3 and HIF-1 and it was mainly characteristic for granular anti-STAT3 staining and rarely for diffuse HIF-1alpha expression. HIF-1alpha, Ob and ObR presented cytoplasmic granular immunoreactivities. Positive staining for STAT3, HIF-1, Ob and ObR occurred in 75%, 79%, 60% and 31% of cancers, respectively. Anti-STAT3 staining did not significantly vary with grading, staging and patients' age. STAT3 correlated with Ob (p=0.048, r=0.290) and with HIF-1alpha (p=0.004, r=0.407) in all cancers but it failed to associate with ObR at all. In opposition to the absence of significant relationship between STAT3 and Ob, STAT3 correlated with HIF-1alpha in well differentiated cancers (G1), poorly differentiated tumors (G3), pT1b neoplasms, compound group of pT1c, pT2a, pT2b tumors, and older patients over their sixties. STAT3 mediated signaling pathways that engage leptin and HIF-1alpha could only be partially reflected in correlations between STAT3 and Ob or STAT3 and HIF-1alpha in the examined neoplasms. Nevertheless, STAT3 failed to mark cancer advancement, so progressive significance of STAT3 is questionable in endometrioid adenocarcinomas.
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PMID:Comparison of STAT3 with HIF-1alpha, Ob and ObR expressions in human endometrioid adenocarcinomas. 1857 74

Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin-induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous-endometrial epithelial cells (EEC) (An3Ca, SK-UT2 and Ishikawa), leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1beta); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1beta was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen-activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin-induced cell signaling pathways in endometrial cancer cells.
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PMID:Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells. 1879 54

Obesity is a risk factor for endometrial cancer in pre- and post-menopausal women. Leptin, an adipocyte-derived hormone, in addition to the control weight homeostasis, is implicated in multiple biological actions. A recent study demonstrated that leptin promotes endometrial cancer growth and invasiveness through STAT/MAPK and Akt pathways, but the molecular mechanism involved in such processes still needs to be elucidated. In an attempt to understand the role of leptin in regulating endometrial cancer cells proliferation, we have demonstrated that leptin treatment reduced the numbers of cells in G0/G1-phase while increased cell population in S-phase. This effect is associated with an up-regulation of cyclin D1 together with a down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Mutagenesis studies, eletrophoretic mobility shift, and chromatin immunoprecipitation analysis revealed that signal transducers and activators of transcription 3 (STAT3) and cyclic AMP-responsive element (CRE) binding protein motifs, within cyclin D1 promoter, were required for leptin-induced cyclin D1 expression in Ishikawa endometrial cancer cells. Silencing of STAT3 and CREB gene expression by RNA interference reversed the up-regulatory effect of leptin on cyclin D1 expression and cells proliferation. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa cells, thus establishing a direct association between obesity and endometrial tumorogenesis.
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PMID:Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation. 1898 90

Hyperleptinemia is a common feature of obese women who have a higher risk of endometrial cancer than women with normal weights, and epidemiologic studies have suggested a correlation between obesity and endometrial carcinoma. Therefore, understanding of the molecular mechanism involved in leptin signaling transduction is important in endometrial cancer prevention and treatment. In this study, both isoforms of the leptin receptor (Ob-R), the long form (Ob-Rb) and short form (Ob-Ra), were detected as being expressed in six endometrial cancer cell lines with various differentiation status by western blotting, and Ob-Ra was found to be more abundant than Ob-Rb in these cells. Moreover, the expressions of both isoforms were inversely correlated with histoprognostic grading. We also showed that leptin stimulated cell proliferation and induced activations of signal transducers and activators of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK1/2), AKT, and cyclooxygenase (COX)-2 in endometrial cancer cells dose-dependently by [(3)H] thymidine incorporation assay and western blotting. Leptin-stimulation resulted in increased expression of COX-2 mRNA and prostaglandin E2 (PGE2) production of endometrial cancer cells by reverse transcription-polymerase chain reaction and enzyme immunoassay, respectively, which was effectively blocked by pharmacological inhibitors of Janus tyrosine kinase 2 (JAK2), AG490; of mitogen-activated protein kinase (MAPK) kinase, U0126; of phosphatidylinositol 3-kinase (PI3K), LY294002; and of COX-2, NS398. These results suggest that leptin promotes cell proliferation of endometrial cancer cells via the aforementioned multiple signal-transduction pathways. Leptin-induced functional activation of COX-2 is JAK2/STAT3-, MAPK/ERK-, and PI3K/AKT-dependent, indicating that COX-2 may be a critical factor of endometrial carcinogenesis in obesity.
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PMID:Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. 1915 13

A mathematical model based on principles of multifactor analysis was developed to predict clinical outcome of endometrial hyperplasia (EH) in patients with metabolic syndrome (80). Seventy-seven factors--anthropometric, clinical, anamnestic, hormono-metabolic, immunohistochemical, etc.--were included. Evaluation of the most informative indices integrated with the discriminative model showed that anthropometric (waist and hip circumference, sagittal diameter, etc.) and clinico-anamnestic (age, age of secondary sexual characters appearance, body weight at birth, suckling pattern, etc.) ones are of similar significance. A profile of hormono-metabolic parameters (cholesterol-low density lipoprotein, leptin, testosterone, progesterone and fasting glucose levels) helped identify a wide range of EH-related disorders in patients with metabolic syndrome. Consistently with the literature data, level of PTEN expression pointed to the presence of this tumor's suppressor in most EH cases which was matched by absence of its expression in endometrial carcinoma. Our model provided high sensitivity (89%) and specificity (82%) in predicting risk of progression in patients with endometrial hyperplasia and metabolic syndrome.
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PMID:[Evaluation of risk of progression of endometrial hyperplasia in patients with metabolic syndrome]. 2113 46


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