leptin and Endometrial-Neoplasms

The objective of the study was to document the effect of adipocytokines on endometrial cancer progression. A search of the databases CINAHL, Medline, PubMed, Cochrane, Web of Science, Embase and Google Scholar was performed for English language articles from January 2000 to December 2020 using the keywords: (Endometrial cancer) AND (progression OR metastasis) AND (adipocytokine OR adiponectin OR leptin OR visfatin OR IL-6 OR TNF-α OR adipokine OR cytokine). Forty-nine studies on adipocytokines have been included in this review. Adiponectin has been linked with anti-proliferative and anti-metastatic effects on endometrial cancer cells and is associated with a better prognosis. Leptin, visfatin and resistin are linked to the stimulation of endometrial cancer growth, proliferation, invasion and metastasis and are associated with worse prognosis or with a higher grade/stage of endometrial cancer. IL-6, Il-11, IL-31, IL-33, TNF-α, TGF-β1, SDF-1 and CXCR are involved in endometrial cancer cell growth and metastasis or involved in epithelial mesenchymal transformation (EMT) or associated with advanced disease. Adipocytokines have been found to directly impact endometrial cancer cell proliferation, invasion and migration. These molecules and their signalling pathways may be used to determine prognosis and course of the disease and may also be exploited as potential targets for cancer treatment and prevention of progression.

Topics: Adipokines; Adiponectin; Disease Progression; Endometrial Neoplasms; Female; Humans; Interleukin-6; Leptin; Nicotinamide Phosphoribosyltransferase; Tumor Necrosis Factor-alpha

Endometrial cancer is the most common malignancy of the female genital tract. Obesity is a strong risk factor for endometrial cancer. Adipose tissue is an active endocrine organ that synthesizes biologically active cytokine peptides, called adipokines. Adiponectin and leptin are the main cytokines of adipose tissue, which may influence the development of metabolic diseases and carcinogenesis. In this scenario, we describe the role of leptin and adiponectin in the development of endometrial cancer. A better understanding of the signalling pathway of these cytokines in endometrial cancerogenesis will provide an opportunity for effective target therapy and may be usable in fertility-sparing treatment. In the future, clinical trials focusing on adipokines, molecular biology, and genetics of the tumour will be needed.

Topics: Adipokines; Adiponectin; Cytokines; Endometrial Neoplasms; Female; Humans; Leptin

To investigate the association between circulating levels of adipocytokines (adiponectin, leptin, tumour necrosis factor alpha (TNFα), interleukin 6 (IL-6)) and growth factors (insulin-like growth factor I (IGF-I) and II (IGF-II)), and the risk of endometrial cancer.. Cochrane, CINAHL, Embase, Medline and Web of Science were searched for English-language manuscripts published between January 2000 and August 2018 using the following string of words: cancer and endometrial and (obesity or BMI) and (adiponectin or TNF* or IGF-I or IGF-II or IL-6 or leptin).. Twenty articles were included in this meta-analysis, which corresponded to 18 studies involving 2921 endometrial carcinoma cases and 5302 controls. Fourteen articles reported circulating levels for adiponectin, seven for leptin, three for TNFα, three for IL-6 and one for IGF-I. No article reported values for IGF-II. Patients with circulating adiponectin levels in the highest tertile had decreased endometrial cancer risk compared to women with levels in the lowest tertile, (summary of odds ratio (SOR) 0.51, 95% confidence interval (CI): 0.38-0.69, p < 0.00001). Women with circulating leptin concentrations in the highest tertile had increased endometrial cancer risk compared to women with concentrations in the lowest tertile (SOR 2.19, 95% CI: 1.45-3.30, p = 0.0002). There was no difference in cancer risk between participants with the highest TNFα and IL-6 levels compared to the lowest levels (SOR 1.27, 95% CI: 0.88-1.83, p = 0.20 and SOR 1.20, 95% CI: 0.89-1.63, p = 0.23, respectively).. Endometrial cancer risk is inversely affected by adiponectin and leptin levels. There appears to be no relationship between TNFα and IL-6 and the overall risk of endometrial cancer.

Topics: Adiponectin; Case-Control Studies; Endometrial Neoplasms; Female; Humans; Interleukin-6; Leptin; Risk Factors; Tumor Necrosis Factor-alpha

We performed this meta-analysis of epidemiologic studies to investigate the associations between circulating adiponectin, leptin and adiponectin-leptin (A/L) ratio and endometrial cancer risk. Relevant manuscripts were identified by searching PubMed and ISI Web of Science databases as well as by manual searching the references cited in retrieved manuscripts. Random-effects models were used to estimate summary odds ratio (SOR) and 95% confidence intervals (CIs) for aforementioned associations. Fourteen manuscripts with 13 studies (five nested case-control and eight case-control studies) cumulatively involving a total of 1,963 endometrial cancer cases and 3,503 noncases were included in the analyses. Overall, comparing persons with circulating concentrations of adiponectin, leptin and A/L ratio in the top tertile with persons with concentrations of these biomarkers in the bottom tertile yielded SORs of 0.47 (95% CI: 0.34-0.65; I(2)  = 63.7%; n = 13), 2.19 (95% CI: 1.44-3.31; I(2)  = 64.2%; n = 7),and 0.45 (95% CI: 0.24-0.86; I(2)  = 90.1%; n = 5), respectively. Notably, there was an 18% reduction in risk for per each 5 μg/mL increment in circulating adiponectin concentrations (SOR = 0.82; 95% CI: 0.74-0.90; I(2)  = 49%; n = 8). Stratifying by study characteristics and whether these studies considered or adjusted for potential confounders, the findings were robust in the analyses of circulating adiponectin and leptin. No evidence of publication bias was detected. In conclusion, the findings from this meta-analysis suggest that increased circulating adiponectin and A/L ratio or decreased leptin concentrations were associated with reduced risk of endometrial cancer. Further prospective designed studies are warranted to confirm our findings.

Topics: Adiponectin; Databases, Bibliographic; Endometrial Neoplasms; Female; Humans; Leptin; Prospective Studies; Retrospective Studies; Risk Factors

Endometrial cancer is one of the main cancers occurring in industrialized countries. According to the National Cancer Registry in Bulgaria, cancer of the uterine body occupies 8.6% from all cancers in women and ranks second in frequency. It is found that over weight and obesity are a major risk factor for the development of endometrial cancer and the mortality associated with it. Adipose tissue is seen as endocrine organ, synthesizing so called adipocytokine - leptin, adiponectin, vistafin, that play a key role in the carcinogenesis of endometrial cancer and can be used as new markers for establishing the potential risk of this disease. The link between obesity, insulin resistance and endometrial cancer that has been proven, determines it as a socially significant disease. All this makes it necessary to clarify and specify the role of obesity in endometrial carcinogenesis and the development of strategies for the prevention and early diagnosis.

Topics: Adiponectin; Adipose Tissue; Bulgaria; Carcinogenesis; Endometrial Neoplasms; Endometrium; Female; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors

Previous studies suggested that high leptin level might increase risk of endometrial cancer, but available data were conflicting and whether high leptin level was an independent risk factor of endometrial cancer was still unclear. Therefore, a meta-analysis was performed to assess whether high leptin level was an independent risk factor of endometrial cancer.. PubMed, Web of Science, and Embase databases were searched for epidemiological studies published up to June 26, 2014. The pooled risk ratio (RR) with 95% confidence interval (95%CI) was used to assess the association between leptin level and risk of endometrial cancer.. Six studies with a total of 3136 individuals were finally included into the meta-analysis. Meta-analysis of total 6 studies showed that high leptin level was associated with increased risk of endometrial cancer (RR = 2.55, 95%CI 1.91-3.41, P < 0.001). After adjusting for confounding factors, high leptin level was also associated with increased risk of endometrial cancer (RR =1.59, 95%CI 1.27-1.98, P < 0.001). Sensitivity analysis proved the stability of the pooled estimates. The RR of endometrial cancer was 1.10 (95%CI, 1.03-1.18, P = 0.005) per 5 ng/mL increment in leptin levels. There was no obvious risk of publication bias (P Egger = 0.54).. Our findings suggest that high leptin level is an independent risk factor of endometrial cancer. More prospective studies are needed to further confirm the association in the future.

Topics: Case-Control Studies; Endometrial Neoplasms; Epidemiologic Studies; Female; Humans; Leptin; Risk; Risk Factors

There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.

Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Colorectal Neoplasms; Endometrial Neoplasms; Esophageal Neoplasms; Female; Humans; Kidney Neoplasms; Leptin; Male; Neoplasms; Obesity; Pancreatic Neoplasms; Prostatic Neoplasms; Thyroid Neoplasms

Endometrial cancer risk is strongly influenced by obesity, but the mechanisms of action remain unclear. Leptin and adiponectin, secreted from adipose tissue, reportedly play a role in such carcinogenic processes as cell proliferation, angiogenesis, and insulin regulation. In this case-control study, nested within the Breast and Bone Follow-up of the Fracture Intervention Trial (n=15,595), we assessed pre-diagnostic serum leptin, total adiponectin, and high-molecular-weight (HMW) adiponectin in relation to endometrial cancer among postmenopausal women. During the 10-year follow-up, 62 incident endometrial cases were identified and matched to 124 controls on age, geographical site, time of fasting blood draw at baseline (1992-1993), and trial participation status. Adipokines and C-peptide were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated via conditional logistic regression, with exposures categorized in tertiles (T). Multivariable models considered C-peptide, BMI (kg/m(2)), and estradiol (E2) as potential confounders. Endometrial cancer risk was significantly associated with higher leptin levels, adjusted for E2 and C-peptide (OR(T3 vs T1)=2.96; 95% CI, 1.21-7.25; P trend <0.01). After further adjustment for BMI, the estimates were attenuated and the positive trend was no longer statistically significant (OR(T3 vs T1)=2.11; 95% CI, 0.69-6.44; P trend=0.18). No significant associations were observed with adiponectin or HMW adiponectin and endometrial cancer. Our findings with leptin suggest that the leptin-BMI axis might increase endometrial cancer risk through mechanisms other than estrogen-driven proliferation. Continued exploration of these pathways in larger prospective studies may help elucidate mechanisms underlying observed obesity-endometrial cancer associations.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Body Mass Index; C-Peptide; Case-Control Studies; Endometrial Neoplasms; Estrogens; Female; Humans; Leptin; Longitudinal Studies; Middle Aged; Obesity; Postmenopause; Prognosis; Risk Factors

Mechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women.. We used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis.. For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-<25 kg/m. Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity-associated cancer risk in postmenopausal women.

Topics: Adiposity; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Endometrial Neoplasms; Estradiol; Fasting; Female; Humans; Insulin; Leptin; Obesity; Postmenopause; Risk Factors

Topics: Adipokines; Adiponectin; Body Mass Index; Carcinoma, Renal Cell; Colorectal Neoplasms; Correlation of Data; Endometrial Neoplasms; Female; Genome-Wide Association Study; Humans; Leptin; Mendelian Randomization Analysis; Obesity; Ovarian Neoplasms; Pancreatic Neoplasms; Plasminogen Activator Inhibitor 1; Principal Component Analysis; Receptors, Leptin; Risk Factors

Obesity increases the risk of developing cancers for both males and females. This study investigated potential crosstalk between estradiol and leptin signaling pathways within the endometrium of high-fat-diet-induced obese ovariectomized mice to gain insight into possible links between obesity and endometrial cancer. We administered 17-β estradiol (0.2 μg/mouse subcutaneously) and/or recombinant mouse leptin (1 μg/g Bwt intraperitoneally.,) for 20 h to high-fat-diet-induced obese ovariectomized mice. The uterine tissues of experimental animals after treatments were studied by histological, immunohistochemical, quantitative real-time PCR (gene/miRNAs), and methylation-specific PCR analyses. Quantitative real-time PCR analysis revealed significantly increased expression of Cyclin d1, Esr1, Igf1, Igfbp2, Vegf, Oct4, and Pgr after estradiol and leptin co-treatment. Methylation-specific PCR results indicated that the hormonal dependent transcriptional regulation of Vegf, Igf1, and Pgr is independent of promoter methylation. The decreased expression of mmu- miR-204-5p after estradiol and leptin treatments correlated with the increased expression of long non-coding RNA Neat1. Insilico analysis confirmed the interaction of Neat1 and mmu- miR-204-5p and gene targets of mmu-miR-204-5p, including Igf1 were analyzed in this study. Immunohistochemical analyses revealed subcellular localization and increased expression of ESR, VEGF, phospho-Estrogen Receptor-α (pTyr537), and LEPR proteins following estradiol and leptin exposure. Overall, the data from our in vivo studies suggest the regulation of Neat1-mmu-miR-204-5p- Igf1 axis and associated gene expression changes in uterine tissue after estradiol and leptin co-treatment. In humans, long-term exposure to estradiol and leptin can alter endometrial homeostasis through the NEAT1-miR-204-5p-Igf1 axis and favor carcinogenic pathways, which provide mechanistic insight into the obesity-associated endometrial cancer.

Topics: Animals; Diet, High-Fat; Endometrial Neoplasms; Estradiol; Estrogens; Female; Gene Expression Regulation; Humans; Insulin-Like Growth Factor I; Leptin; Mice; Mice, Obese; MicroRNAs; Obesity; Ovariectomy; RNA, Long Noncoding

This research aimed to assess the impact of cisplatin, depending on the concentration and exposure time, on the expression pattern of leptin in an endometrial cancer cell line. Ishikawa endometrial cancer cell cultures were incubated with cisplatin, at concentrations of 2.5-10 µM, or leptin in the concentration range 10-40 ng/mL, and for durations of 12, 24 and 48 h compared with the control. The microarray techniques: RTqPCR; ELISA; and RNAi assay were used. Statistical analysis was performed at

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Caspases; Cell Line, Tumor; Cell Size; Cisplatin; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; Leptin; Receptors, Leptin; RNA Interference; STAT3 Transcription Factor

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Cohort Studies; DNA Mismatch Repair; DNA Polymerase II; Endocrine System; Endometrial Neoplasms; Endometrium; Estradiol; Female; Humans; Hysterectomy; Insulin; Leptin; Middle Aged; Mutation; Obesity; Poly-ADP-Ribose Binding Proteins; Testosterone

The chemopreventive effects of black raspberries (BRBs) have not been studied in endometrial tumorigenesis. Here, they are examined in a mouse model of endometrial cancer.. Wild-type and Pten heterozygous (+/-) female mice are weaned at 3 weeks and fed with four AIN-93G diets: 93G; 93G+5% BRBs powder; high-fat (HF); and HF+5% BRBs. Body weight and diet consumption are recorded weekly until the mice are euthanized at 28 weeks of age. Mice fed with HF diets are found to significantly gain body weight over time. BRBs are not found to affect the development of obesity. Mice in the HF+BRBs group consume less food than the HF-only mice. HF+BRBs diets suppress uterine tumor initiation and promotion more than the HF-only diet by inhibiting cell proliferation. It also reduces HF-induced levels of plasma leptin and 17β-estradiol (E2). Urolithin A, a metabolite of BRBs, suppresses cell proliferation induced by leptin and E2.. BRBs are preventive in HF-mediated uterine tumorigenesis because they suppress cell growth and plasma leptin and E2 levels.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Diet, High-Fat; Endometrial Neoplasms; Estradiol; Female; Leptin; Mice; PTEN Phosphohydrolase; Rubus

Type-II Endometrial Cancer (EMC) is one of the most common types of gynaecological cancer affecting more than 2.7 million people worldwide. Clinical evidence shows that adipokines levels are abnormally altered in Type-II EMC and reported to be one of the major responsible factor for uncontrolled proliferation and metastasis in Type-II EMC. Reversing the altered adipokine levels, therefore, help to control Type-II EMC proliferation and metastasis. In the present hypothesis we focus on the possible role of Thiazolidinediones in favourably altering the adipokine levels to benefit in the management of Type-II EMC.

Topics: Adipokines; Adiponectin; Animals; Cell Proliferation; Endometrial Neoplasms; Female; Gene Expression Regulation; Humans; Leptin; Mice; Models, Biological; Neoplasm Metastasis; Resistin; Thiazolidinediones

The expression of NILCO molecules (Notch, IL-1, and leptin crosstalk outcome) and the association with obesity were investigated in types I and II endometrial cancer (EmCa). Additionally, the involvement of NILCO in leptin-induced invasiveness of EmCa cells was investigated.. The expression of NILCO mRNAs and proteins were analyzed in EmCa from African-American (. NILCO molecules were expressed higher in type II EmCa, regardless of ethnic background or obesity status of patients. NILCO proteins were mainly localized in the cellular membrane and cytoplasm of type II EmCa. Additionally, EmCa from obese African-American patients showed higher levels of NILCO molecules than EmCa from lean patients. Notably, leptin-induced EmCa cell invasion was abrogated by NILCO inhibitors.. Type II EmCa expressed higher NILCO molecules, which may suggest it is involved in the progression of the more aggressive EmCa phenotype. Obesity was associated with higher expression of NILCO molecules in EmCa. Leptin-induced cell invasion was dependent on NILCO. Hence, NILCO might be involved in tumor progression and could represent a new target/biomarker for type II EmCa.

Topics: Adenocarcinoma, Papillary; Aged; Antibodies; Asian People; Black People; Carcinoma, Endometrioid; Cell Line, Tumor; Cell Proliferation; Cystadenocarcinoma, Serous; Diamines; Disease Progression; Endometrial Neoplasms; Endometrium; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-1; Leptin; Middle Aged; Neoplasm Staging; Obesity; Protein Isoforms; Receptor, Notch1; Signal Transduction; Thiazoles

The aim of this study was to analyse the frequencies of genotypes and alleles of Single Nucleotide Polymorphism (SNP) -2548 G/A (rs12112075) of leptin gene (LEP) and an attempt to evaluate the effect this DNA marker has on endometrial cancer (EC) and uterine leiomyomas (UL).. The study comprised 120 patients treated for endometrial cancer and 90 patients treated for uterine leiomyomas. 90 disease-free individuals were used as controls. In total, 300 patients were investigated in this research.. In this paper we have demonstrated that genotype AG of SNP -2548 G/A of LEP may reduce the risk of developing endometrial cancer, whereas allele A itself may be a risk factor of this malignancy. No association was found between the studied polymorphism and uterine leiomyomas.. -2548 G/A SNP of LEP may play a significant role in the development of EC, however, uterine leiomyomas are not associated with this DNA marker.

Topics: Alleles; Body Mass Index; Case-Control Studies; Endometrial Neoplasms; Female; Genetic Markers; Genotype; Humans; Leiomyoma; Leptin; Middle Aged; Obesity; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Risk Factors; Uterine Neoplasms

Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.

Topics: Adiponectin; Animals; Caloric Restriction; Cyclin-Dependent Kinase Inhibitor p27; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Risk; Signal Transduction; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a novel molecular constituent of tricellular contacts that have a barrier function for the cellular sheet. LSR recruits tricellulin (TRIC), which is the first molecular component of tricellular tight junctions. Knockdown of LSR increases cell motility and invasion of certain cancer cells. However, the behavior and the roles of LSR in endometrial cancer remain unknown. In the present study, we investigated the behavior and roles of LSR in normal and endometrial cancer cells in vivo and in vitro. In endometriosis and endometrial cancer, LSR was observed not only in the subapical region but also throughout the lateral region as well as in normal endometrial epithelial cells in the secretory phase, and LSR in the cancer was reduced in correlation with the malignancy. Knockdown of LSR by the siRNA in cells of the endometrial cancer cell line Sawano, induced cell migration, invasion and proliferation, while TRIC relocalized from the tricellular region to the bicellular region at the membrane. In Sawano cells and normal HEEs, a decrease of LSR induced by leptin and an increase of LSR induced by adiponectin and the drugs for type 2 diabetes metformin and berberine were observed via distinct signaling pathways including JAK2/STAT. In Sawano cells, metformin and berberine prevented cell migration and invasion induced by downregulation of LSR by the siRNA and leptin treatment. The dissection of the mechanism in the downregulation of endometrial LSR during obesity is important in developing new diagnostic and therapy for endometrial cancer.

Topics: Adiponectin; Berberine; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Endometrial Neoplasms; Endometrium; Epithelial Cells; Female; Gene Knockdown Techniques; Humans; Hypoglycemic Agents; Leptin; MARVEL Domain Containing 2 Protein; Metformin; Neoplasm Invasiveness; Receptors, Lipoprotein; Risk Factors; RNA Interference; RNA, Small Interfering; Tight Junctions; Transcription Factors

Metformin reduces cancer incidence and improves overall survival in diabetic patients. In preclinical studies, metformin decreases endometrial cancer (EC) cell growth by activation of AMPK/mTOR inhibition. We sought to determine the effects of metformin on serum/tumor biomarkers in women with EC.. In this prospective trial, newly diagnosed EC patients underwent pre-treatment blood draw/endometrial biopsy, were administered oral metformin 850mg daily for ≥7days, and underwent post-treatment blood draw/definitive surgery. Pre- and post- serum analyses were performed. Tumor samples were evaluated for changes in AMPK, PI3K/AKT pathway, proliferation, and apoptosis by immunohistochemistry.. In this prospective window of opportunity study, we demonstrated that relevant serum and molecular changes occur in patients with newly diagnosed EC after a short course of metformin. Ongoing clinical trials will help determine the appropriate role for metformin in the treatment of women with EC.

Topics: Adult; Aged; AMP-Activated Protein Kinases; Apoptosis; Biomarkers, Tumor; Carcinoma, Endometrioid; Caspase 3; Cell Proliferation; Cytokines; Endometrial Neoplasms; Endometrium; Female; GPI-Linked Proteins; Humans; Hypoglycemic Agents; Immunohistochemistry; Insulin; Insulin-Like Growth Factor I; Ki-67 Antigen; Lectins; Leptin; Metformin; Middle Aged; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Phosphoproteins; Prospective Studies; Proto-Oncogene Proteins c-akt

Leptin has recently been shown to affect cancer proliferation and invasion through multiple pathways. In the current study, we investigated the role of leptin in endometrial carcinoma (EC) apoptosis and the underlying mechanisms of action.. Immunoprecipitation was used to characterize leptin receptor expression in EC lines. The levels of nuclear factor κB-inducing kinase (NIK)/IκB kinase (IKK) signaling proteins were analyzed using Western blot. In addition, Western blot and immunohistochemical analyses were used to detect the hierarchy of these proteins in EC tissues. Quantitative cancer cell apoptosis assay was performed using flow cytometry after incubation of cells with Annexin-V/fluorescein/propidium iodide, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide or staining of cancer cell DNA fragments with propidium iodide.. Leptin induced a decrease in apoptosis in Ishikawa and HEC-1A EC cells, partly through nuclear factor κB activation via phosphorylation in the IKK/NIK pathway. Inhibition of IKK or NIK partly neutralized this suppression of apoptosis. Expression levels of leptin receptors (Ob-Rs) and IKK/NIK signaling proteins were higher in poorly and moderately differentiated than in well-differentiated EC tissues, and higher Ob-Rs expression was observed in clinical stages II and III, compared with stage I EC (P = 0.012). High serum leptin concentration displayed mild correlation (r = 0.23, P = 0.035) with degree of EC differentiation.. Leptin inhibits EC apoptosis partly through activation of the NIK/IKK pathway in vitro. Ob-Rb overexpression seems to facilitate EC progression.

Topics: Apoptosis; Blotting, Western; Body Mass Index; Cell Proliferation; Endometrial Neoplasms; Female; Humans; I-kappa B Kinase; Immunoenzyme Techniques; Immunoprecipitation; Leptin; Membrane Potential, Mitochondrial; Neoplasm Staging; NF-kappa B; NF-kappaB-Inducing Kinase; Phosphorylation; Prognosis; Protein Serine-Threonine Kinases; Receptors, Leptin; Signal Transduction; Tumor Cells, Cultured

The aim of the study was to investigate the serum adipokine levels and expression of adipokine receptors (AdipoR1, AdipoR2) in patients with endometrial and colon cancer in relation with the main clinical morphological parameters (tumor invasion, lymph node involvement). The study included 60 endometrial cancer patients with I-II Stage and 31 patients with colon cancer (T2-4N0-2M0). Serum adipokine levels, the level of soluble form of the leptin receptor (sOb-R) and AdipoR1 and AdipoR2 expression were evaluated with ELISA. In endometrial cancer serum leptin and adiponectin levels were associated not only with metabolic disorders but also with cervical invasion. In colon cancer serum leptin level was associated with lymph node involvement. The data obtained showed the potential implication of serum adipokines into tumor invasion and metastasis. In both sites intratumoral levels of AdipoR1 H AdipoR2 were not associated with the presence of metabolic syndrome. The AdipoR1 level was related with myometrial invasion. In colon cancer patients, AdipoR1 and AdipoR2 expressions were associated with lymph node involvement, and AdipoR1 expression was correlated with tumor size. The obtained results demonstrated involvement of adipose tissue hormones (leptin and adiponectin) and adiponectin receptors (AdipoR1 and AdipoR2) in tumor growth, invasion and lymphogenic metastasis.

Topics: Adipokines; Adiponectin; Adult; Aged; Cervix Uteri; Colonic Neoplasms; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Lymphatic Metastasis; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Receptors, Adiponectin

The expressions of leptin and its receptor (ObR) have been observed in human endometrial cancer (EC) cells, and leptin can promote the proliferation of EC cells. However, the correlation between leptin and ObR expressions in EC and the clinicopathology of EC is still unclear.. This study investigated the correlation between the expressions of leptin and ObR in EC and the clinicopathology of EC.. Immunohistochemistry was used in this study. The correlation between the expressions of leptin and ObR in EC and the clinicopathology of EC was analyzed.. In the EC specimens, the expressions of leptin and ObR were positively correlated with the invasiveness of the cancer and the obesity of patients, but inversely correlated with histological grade. The percentages of leptin and ObR were significantly higher in the patients with lymph node metastasis. Positive expression of leptin and ObR was associated with poorer prognosis (3-year survival rate). Moreover, the expression of leptin and ObR was associated with positive expression of estrogen receptor.. Leptin and ObR are overexpressed in EC, and their expressions are associated with malignancy, invasion, and metastasis of EC. Thus, leptin and ObR may be important indicators in EC.

Topics: Adult; Aged; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Middle Aged; Obesity; Prognosis; Receptors, Estrogen; Receptors, Leptin

The adipose cell has been considered an inert cell from a secretory point of view. Studies over the past years have confirmed the capacity of the adipocyte to synthesize many substances including: adiponectin, leptin, which integrate multiple metabolic and endocrine signals. In the context of endometrial cancer, abdominal obesity as a risk factor is associated with a chronic inflammatory process, confirmed by the increase of inflammatory markers. The study aimed to identify a correlation between abdominal obesity, plasma adipokine levels and endometrial cancer.. Two groups of patients were included in the study: group I - 44 patients diagnosed with endometrial cancer, group II - 44 patients without gynecological pathology or inflammatory disorders. After the performance of clinical examination and anthropometric measurements, abdominal fat was determined by dual X-ray absorptiometry and plasma adiponectin and leptin levels were measured.. A significantly higher abdominal fat and leptin value was found in the group of patients in with endometrial cancer (p < 0.0001), while the plasma adiponectin level was significantly lower, compared to the control group (p < 0.0001). Abdominal fat was in a negative linear correlation with the plasma adiponectin level and in a positive linear correlation with the plasma leptin level.. The measurement of adiponectin and leptin levels associated with the determination of abdominal adipose tissue can be a useful predictor factor for endometrial cancer.

Topics: Abdominal Fat; Adipocytes; Adiponectin; Adiposity; Aged; Case-Control Studies; Endometrial Neoplasms; Female; Humans; Leptin; Middle Aged; Predictive Value of Tests

We conducted a comparative investigation of the hormonal status (LH, FSH, estradiol, progesterone, testosterone, prolactin, SHBG), energy status (leptin, ghrelin, insulin), and carbohydrate and lipid metabolism in patients with endometrial hyperplasia and neoplasia (168 patients) with or without metabolic syndrome in the background. Patients with metabolic syndrome had a high frequency of elevated estrogen (72%), testosterone (65%), insulin (81%), leptin (68%). There was a marked increase in the basal level of luteinizing hormone, prolactin, index, LH/FSH, but decrease in FSH and progesterone. There were significant changes in carbohydrate and lipid metabolism. The possible mechanisms for the contribution of the investigated factors to the development of the pathological processes in the endometrium are presented.

Topics: Adult; Aged; Dietary Carbohydrates; Endometrial Hyperplasia; Endometrial Neoplasms; Estradiol; Female; Follicle Stimulating Hormone; Ghrelin; Gonadal Steroid Hormones; Humans; Insulin; Leptin; Lipid Metabolism; Luteinizing Hormone; Metabolic Syndrome; Middle Aged; Progesterone; Prolactin; Sex Hormone-Binding Globulin; Testosterone

Leptin, a multifunctional peptide hormone encoded by the obese (ob) gene, plays an important role in modulating lipid metabolism and energy equilibrium. Leptin reportedly acts as a cell growth factor and enhances the proliferation of various tumors. We investigated the effect of leptin on aromatase (P450arom) expression and estradiol (E2) formation in a model of endometrial carcinoma.. We established a co-culture model of endometrial fibroblasts and the Ishikawa endometrial carcinoma cell line. P450arom mRNA and protein expression were measured with RT-PCR and immunoblotting, respectively, before and after leptin treatment. The effect of leptin on estradiol formation in endometrial carcinoma cells was also detected with a radioimmunological method.. P450arom mRNA expression was increased in co-cultures treated with 100 ng/ml leptin (P<0.01). Estradiol synthesis was induced when androstenedione was added to the culture medium, and significantly higher estradiol concentration was observed in co-cultures treated with 100 ng/ml leptin,. Leptin is an important component of the microenvironment and stimulates endometrial carcinoma cell proliferation via enhancing P450arom expression and estradiol synthesis.

Topics: Aromatase; Carcinoma; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Endometrial Neoplasms; Estradiol; Female; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Leptin

Obesity is associated with circulating levels of adiponectin and leptin and endometrial cancer risk. Little is known about whether single nucleotide polymorphisms (SNPs) in the genes that encode adiponectin (ADIPOQ), leptin (LEP), adiponectin receptor 1 (ADIPOR1), adiponectin receptor 2 (ADIPOR2), and leptin receptor (LEPR) are associated with endometrial cancer.. The authors selected 87 tagging SNPs to capture common genetic variants in these 5 genes. These SNPs were evaluated in 1028 endometrial cancer cases and 1932 community controls recruited from Chinese women. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).. Three of the 10 SNPs evaluated in the ADIPOQ gene were significantly associated with reduced cancer risk. The OR for women homozygous for the minor allele (A/A) for rs3774262 was 0.68 (95% CI, 0.48-0.97) compared with women homozygous for the major allele (G/G). Similar results were found for SNPs rs1063539 and rs12629945 in ADIPOQ, which were in linkage disequilibrium with rs3774262. These associations became nonsignificant after Bonferroni correction was applied. Controls with the minor allele A at rs3774262 had lower weight, smaller waist and hip circumferences, and lower body mass index than controls with the major allele G (all P < .05). Women homozygous for the minor allele (T/T) of rs2071045 in the LEP gene also had significantly lower risk (OR, 0.70; 95% CI, 0.54-0.90) than women homozygous for the major allele (C/C). No other SNPs in the LEP, ADIPOR1, ADIPOR2, or LEPR genes were found to be associated with cancer risk.. Although a chance finding cannot be ruled out, the consistency of findings for gene-endometrial cancer risk and gene-obesity measurements suggests that genetic polymorphisms in the ADIPOQ gene may play a role in endometrial cancer development.

Topics: Adiponectin; Endometrial Neoplasms; Female; Genetic Predisposition to Disease; Humans; Leptin; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Receptors, Adiponectin; Receptors, Leptin; Risk Factors

Obesity is a well-established risk factor for endometrial cancer, due in part to the adipokines generated by adipose tissue, such as adiponectin (also known as Acrp30) and leptin, which are associated with many endocrine-related cancers. Recent reports suggested that Acrp30 inhibits leptin-stimulated cell proliferation in HEC-1A and RL95-2 endometrial cancer cell lines, and that the serum leptin/Acrp30 ratio plays an important role in endometrial cancer development. We explored whether Acrp30 could reverse the leptin-induced metastasis phenotype in the SPEC-2 endometrial cancer cell line. Transcripts for Acrp30 receptors (AdipoR1 and AdipoR2) and leptin receptor (Ob-Rb) were detected by quantitative real-time RT-PCR (qRT-PCR) in six endometrial cancer cell lines. Leptin (1 µg/ml) treatment stimulated SPEC-2 cell proliferation by inducing cell cycle arrest and apoptosis, while Acrp30 (10 µg/ml) treatment inhibited the growth of SPEC-2 cells. Importantly, Acrp30 was able to inhibit leptin-induced SPEC-2 cell proliferation. Leptin promoted SPEC-2 cell invasion in a Matrigel transwell assay, while Acrp30 partly suppressed the invasion stimulated by leptin. To investigate the molecular mechanism underlying this phenomenon, we monitored the AMPK and JAK/STAT3 signaling pathways by western blotting and cell immunofluorescence. Acrp30 reduced leptin-induced STAT3 phosphorylation and nuclear translocation via activation of the MAPK pathway. AG490 (JAK/STAT3 inhibitor) reduced MMP-2 and MMP-9 protein levels in cells treated with leptin, while IL-6 (JAK/STAT3 stimulator) and Compound C (AMPK inhibitor) elevated MMP-2 and MMP-9 protein levels in cells treated with Acrp30. In conclusion, we demonstrated that Acrp30 effectively reversed the invasion stimulated by leptin, and AMPK and JAK/STAT3 pathways mediated the invasive phenotype of SPEC-2 cells.

Topics: Adiponectin; AMP-Activated Protein Kinases; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Down-Regulation; Endometrial Neoplasms; Enzyme Activation; Female; Humans; Intracellular Signaling Peptides and Proteins; Janus Kinases; Leptin; Membrane Proteins; Neoplasm Metastasis; Protein Transport; Receptors, Adiponectin; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

To evaluate the correlation between endometrial cancer and adiponectin plasma concentration, leptin plasma concentration as well as adiponectin to leptin index in the population of postmenopausal women with abnormal vaginal bleeding.. An observational study SETTINg: Department of Gynecology and Obstetrics, Specialist Teaching Hospital in Tychy, Poland. Population. 99 women between 47 and 88 years old, in postmenopausal state.. The cases (54 women) were females hospitalized due to postmenopausal vaginal bleeding in whom dilation and curettage (D&C) was performed and endometrial intraepithelial neoplasia (EIN) was diagnosed in anathomopathology. Hysterectomy was then performed in all cases and the endometrial cancer diagnosis was confirmed. The controls (45 women) consists of females with no postmenopausal uterine bleeding in whom endometrial thickness in transvaginal ultrasound was greater than 5 mm. D&C was than performed and no endometrial neoplasia was detected in any of the subjects. Adiponectin and leptin plasma concentration was measured in both groups. Mein outcome measures. The area under the curve, sensitivity, specificity and cutoffs for adiponectin, leptin and adiponectin to leptin index.. Adiponectin, leptin and adiponectin to leptin index were statistically correlated with the risk of endometrial cancer. At the suggested cutoffs, corresponding to the highest accuracy (minimal false-negative and false-positive results), adiponectin to leptin index resulted in the highest sensitivity and specificity compared to adiponectin and leptin alone.. Adiponectin to leptin index due to the highest sensitivity and specificity may be used as a marker of endometrial cancer in postmenopausal women with abnormal vaginal bleeding.

Topics: Adiponectin; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Endometrial Neoplasms; Female; Humans; Leptin; Middle Aged; Postmenopause; Predictive Value of Tests; Sensitivity and Specificity; Uterine Hemorrhage

Since leptin is believed to be a key player in carcinogenesis, a study has been designed to investigate the relationship between leptin levels and endometrial cancer.. A study including 30 patients with endometrial cancer and 30 healthy controls was carried out between November 2008 and July 2009 in Hacettepe University Hospital. All patients with endometrial cancer underwent a complete surgical staging procedure including lymphadenectomy. Preoperative leptin levels of endometrial cancer patients and healthy controls were compared. The relationships between leptin levels and stage, grade, histological type and lymph node status of endometrial cancer cases were evaluated.. The mean serum leptin levels were 16.9 ng/ml among endometrial cancer cases and 19.0 ng/ml among controls (p = 0.32). Of endometrial cancer cases, the mean leptin level was found to be 15.8 ng/ml for Stage I and 18.5 ng/ml for Stage II-IV disease (p = 0.34). The figure was 17.7 ng/ml for endometrioid and 13.2 ng/ml for non-endometrioid type of tumor (p = 0.24). The mean leptin levels of 16.3 ng/ml for grade 1 and 19.9 ng/ml for grade 2-3 tumors were observed (p = 0.07). The cases with positive and negative lymph nodes had leptin levels of 20.2 ng/ml and 16.1 ng/ml, respectively (p = 0.30).. Serum leptin levels in endometrial cancer patients were similar to healthy controls. Leptin did not show any significant correlation with stage, grade, histological type and node metastases in endometrial cancer.

Topics: Adult; Aged; Carcinoma, Endometrioid; Endometrial Neoplasms; Female; Humans; Leptin; Lymphatic Metastasis; Middle Aged; Neoplasm Grading; Neoplasm Staging

Markers of insulin resistance such as the adiponectin:leptin ratio (A:L) and the homeostasis model assessment ratio (HOMA-IR) are associated with obesity and hyperinsulinemia, both established risk factors for endometrial cancer, and may therefore be informative regarding endometrial cancer risk. This study investigated the association between endometrial cancer risk and markers of insulin resistance, namely adiponectin, leptin, the A:L ratio, insulin, fasting glucose, and the HOMA-IR. We analyzed data from 541 incident endometrial cancer cases and 961 frequency age-matched controls in a population-based case-control study in Alberta, Canada from 2002 to 2006. Participants completed interview-administered questionnaires were assessed for anthropometric measures, and provided 8-h fasting blood samples either pre- or postoperatively. Blood was analyzed for concentrations of leptin, adiponectin, and insulin by immunoassay, and fasting plasma glucose levels were determined by fluorimetric quantitative determination. Compared with the lowest quartile, the highest quartile of insulin and HOMA-IR was associated with 64% (95% confidence intervals (CI): 1.12-2.40) and 72% (95% CI: 1.17-2.53) increased risks of endometrial cancer, respectively, and the highest quartile of adiponectin was associated with a 45% (95% CI: 0.37-0.80) decreased risk after multivariable adjustments. Null associations were observed between fasting glucose, leptin and A:L, and endometrial cancer risk. This population-based study provides evidence for a role of insulin resistance in endometrial cancer etiology and may provide one possible pathway whereby obesity increases the risk of this common cancer. Interventions aimed at decreasing both obesity and insulin resistance may decrease endometrial cancer risk.

Topics: Adiponectin; Aged; Biomarkers; Blood Glucose; Case-Control Studies; Endometrial Neoplasms; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Risk

Obesity results in increased mortality from many forms of cancer. We looked at the levels of gene expression for TNFalpha, IL-6, IkappaB kinase (inhibitor of NF-kappaB), CD 68 (glycoprotein expressed on macrophages) and leptin in samples of adipose tissue from individuals with endometrial cancer versus patients with benign conditions. This is a prospective study which included patients of a gynecologic oncology group. A piece of omental tissue was harvested from them during surgery. RNA was purified from all samples. Relative amounts of RNA for IkappaB, TNFalpha, IL-6, CD68 and leptin were calculated. Pearson's correlation method was used to correlate RNA levels with BMI. Logistic regression method was used to compare gene expression for cancer and control groups. The total sample size was 56 (24 endometrial cancer and 32 controls). IkappaB, TNFalpha and IL-6 levels increased linearly with increasing BMI in the control group. There was no correlation of IkappaB, TNFalpha, IL-6 or CD-68 levels with cancer status of the patients. Leptin had a weak protective effect against endometrial cancer (odds ratio = 0.92). Obesity is associated with increased expression of certain inflammatory cytokines in the adipose tissue. However, increased levels of these inflammatory markers in the adipose tissue of the omentum are not associated with presence of endometrial cancer.

Topics: Adipose Tissue; Adult; Aged; Aged, 80 and over; Body Mass Index; Cytokines; Endometrial Neoplasms; Female; Humans; Leptin; Logistic Models; Middle Aged; NF-kappa B; Obesity; Prospective Studies

Obesity is an established risk factor for endometrial cancer. Leptin, a secreted protein of the ob gene by white adipose tissue, plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic cancer cells. However, a direct role for leptin in endometrial cancer has not been demonstrated. In the present study, the effect of leptin on the proliferation of Ishikawa endometrial cancer cells was investigated as well as the possible mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. The expression of leptin receptor (ObRb) in Ishikawa cells was detected by RT-PCR and Western blotting. The cells after serum starvation, were treated by leptin with various concentrations (0, 10, 50, 100, 150 ng/mL) for different durations (6, 12, 24 h). The effect of leptin treatment on cell proliferation was examined by MTT assay. Meanwhile, inhibitory effect of Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) inhibitor AG490 or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 on the proliferation of Ishikawa cells induced by leptin was also studied. Ishikawa cells were treated with 100 ng/mL leptin for various periods (0, 20, 40, 60 min), and the levels of STAT3 phosphorylation and ERK1/2 phosphorylation were examined by Western blotting. The results showed that leptin induced the phosphorylation of STAT3 and the activation of ERK1/2 in a time- and dose-dependent manner in the Ishikawa endometrial cancer cells. Blocking STAT3 phosphorylation with the inhibitor AG490, or blocking ERK1/2 activation by the specific ERK1/2 kinase inhibitor, PD98059, abolished leptin-induced proliferation of Ishikawa cells. In addition, leptin was found to potently induce the invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of STAT3 (AG490) and ERK1/2 kinase (PD98059). These results suggested that leptin promotes endometrial cancer growth and invasiveness by activating STAT3 and ERK1/2 signaling pathways and therefore blocking its action at the receptor level can be a rational therapeutic strategy.

Topics: Adenocarcinoma; Cell Line, Tumor; Cell Proliferation; Endometrial Neoplasms; Enzyme Inhibitors; Female; Flavonoids; Humans; Leptin; MAP Kinase Signaling System; Neoplasm Invasiveness; STAT3 Transcription Factor; Tyrphostins

Obesity is a well-known risk factor for the development of endometrial cancer. Elevated endogenous estrogen and insulin resistance are recognized to be major factors that link obesity and cancer development. However, there is increasing evidence that the adipokines adiponectin and leptin, which are directly produced in adipose tissue, impact several obesity-related cancers. The purpose of the current study was to investigate the relationships of the concentration of leptin, adiponectin, and the leptin-to-adiponectin ratio (L/A ratio) with the endometrial cancer risk in postmenopausal female subjects.. A case-control study was performed in 146 postmenopausal female subjects with endometrial cancer and 150 control subjects with no history of cancer. The serum levels of the adipokines leptin and adiponectin were measured, and the associations of these adipokines and the L/A ratios with the endometrial cancer risk were analyzed.. The leptin levels and the L/A ratios were significantly higher in the incident cases of endometrial cancer (8.2 ± 0.5, 2.05 ± 1.08 ng/ml) than in the controls subjects (4.5 ± 0.5, 0.98 ± 0.18, P<0.0001), whereas the adiponectin levels were significantly lower in the incident cases (6.2 ± 0.4 μg/ml) than in the control subjects (9.0 ± 0.4 μg/ml, P<0.0001). For the incident cases, the serum levels of the adipokines were significantly correlated with the patient body mass index (BMI) (P<0.001 for leptin, P<0.05 for adiponectin), and the leptin levels and the L/A ratios were significantly correlated with the homeostasis model assessment ratio (HOMA-R) and the fasting insulin levels (P<.001). Higher L/A ratios were found to be significantly associated with an increased risk of endometrial cancer [OR (95% CI) for the top vs. the bottom tertile of the L/A ratio was 6.0 (3.2-11.9), P-value<0.0001]. Moreover, the ORs of the L/A ratios were higher than those of leptin or adiponectin alone. The association of the L/A ratios with endometrial cancer risk remained after adjusting for the obesity indices, hypertension, and presence of diabetes mellitus.. The present results suggested that the L/A ratio was independently associated with an increased risk for endometrial cancer development. Additional research will elucidate the molecular mechanisms by which these adipokines are associated with the development of endometrial cancer.

Topics: Adiponectin; Case-Control Studies; Endometrial Neoplasms; Female; Humans; Leptin; Middle Aged; Postmenopause; Risk Factors

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.

Topics: Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; DNA, Neoplasm; Down-Regulation; Endometrial Neoplasms; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Promoter Regions, Genetic; Protein Binding; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Transcriptional Activation

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.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Endometrial Neoplasms; Enzyme Activation; Female; Humans; Immunoassay; Janus Kinase 2; Leptin; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor

Previously, the polymorphism-2548 G/A within the promoter of the leptin (LEP) gene was reported to be associated with overweight and obesity, the factors significantly associated to increased endometrial cancer risk. Leptin has been described to play an important role in signal transduction in endometrial cancer cells indicating that leptin promotes endometrial cancer growth and invasiveness and implicating the JAK/STAT and AKT pathways as critical mediators of leptin action. The aim of the study was to investigate the possible associations of LEP-2548 G/A polymorphism with endometrial cancer and its related traits.. Using PCR with following restriction analysis, we studied 67 endometrial cancer cases (mean age 64.3 +/- 10.3 years) that were enrolled in the study along with 67 controls matched for age, BMI and ethnic origin (mean age 62.1 +/-9.8 years); an additional cohort of 543 healthy individual was recruited to investigate the general population frequencies.. The present study revealed no significant differences between the genotypes or alleles of investigated polymorphism for endometrial cancer risk or its related traits (age of menarche, menopause, number of spontaneous abortions in personal history or waiting time till the onset of the disease) among the groups, thus indicating that the genetic variants of LEP-2548 G/A is not a relevant marker of endometrial cancer risk in this Czech population.. To conclude, the polymorphism LEP-2548 G/A doesn't seem to represent a major genetic marker for endometrial cancer in the studied Czech population; however, it was associated with obesity, which finding is in accordance with previous reports.

Topics: Body Mass Index; Endometrial Neoplasms; Female; Genotype; Humans; Leptin; Middle Aged; Obesity; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; Uterine Neoplasms

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.

Topics: Biomarkers, Tumor; Carcinoma, Endometrioid; Cell Nucleus; Endometrial Neoplasms; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Leptin; Middle Aged; Receptors, Leptin; STAT3 Transcription Factor

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.

Topics: Adenocarcinoma; Blotting, Western; Endometrial Neoplasms; Endometrium; Female; Humans; Interleukin-1beta; Leptin; Leukemia Inhibitory Factor; Neovascularization, Pathologic; Protein Kinases; Receptors, Interleukin-1; Receptors, OSM-LIF; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Leptin levels in serum depending on Body Mass Index (BMI) in patients with endometrial hyperplasia and cancer.. Concentrations of leptin, a hormone secreted by white adipose tissue, correlate strongly with body mass. Leptin interacts with several other hormones, modifies the activities of some enzymes and proinflammatory cytokines, participates in hematopoiesis, thermogenesis, and angiogenesis, and is involved in the control of carbohydrate and lipid metabolism. This study was undertaken to determine whether serum concentrations of leptin in obese patients with endometrial hyperplasia and cancer deviate from values in patients with normal endometrium.. We enrolled 86 obese postmenopausal women, including 40 with endometrial cancer and hyperplasia and 46 with normal endometrium. Depending on BMI, three subgroups were formed: I<30; II = 30-40; III > 40. Leptin concentrations were measured with immunoenzymatic test kits from IBL. Statistical comparison was done with the chi square (chi(2)) test and Statistica software package.. Mean serum concentration of leptin in endometrial cancer and hyperplasia was 16737.1 pg/ml as opposed to 9048.7 pg/ml in patients without endometrial pathology (p<0.0001). Significantly, higher concentrations of leptin were noted in every BMI subgroup of patients with endometrial pathology in comparison to controls (p<0.005).. Leptin appears to participate in proliferative processes of the endometrium. Obesity is an important risk factor in endometrial cancer.

Topics: Biomarkers; Body Mass Index; Case-Control Studies; Chi-Square Distribution; Endometrial Hyperplasia; Endometrial Neoplasms; Female; Humans; Leptin; Middle Aged; Obesity; Postmenopause; Reference Values

Recent studies suggested that Ob (Ob) and its receptor (ObR) could be involved in the pathogenesis of various human malignancies, among others in endometrial cancer. Moreover, hypoxia, which is associated with solid tumors, might stimulate, through hypoxia-inducible factor 1alpha (HIF-1alpha), expression of Ob and ObR. In this article, we analyzed by immunohistochemistry the expression of Ob, ObR, and HIF-1alpha in 60 cases of human endometrial cancer tissues as well as in 25 cases of normal endometria. Additionally, we assessed correlations among studied proteins as well as relationships with selected clinicopathological features of endometrial cancer. Immunoreactivity for Ob, ObR, and HIF-1alpha protein was observed in 56.7%, 30.0%, and 78.3% of endometrial cancers, respectively. The expression of HIF-1alpha showed a significant positive correlation with Ob (P < 0.0001, r = 0.573) and ObR (P = 0.020, r = 0.299). Moreover, we noted positive correlation between Ob and ObR (P = 0.001, r = 0.429). No statistically significant relationship was revealed between Ob, ObR, and HIF-1alpha protein in regard to patient's age, histological grade, and extent of tumor growth (pT). In conclusion, HIF-1alpha, which is related to tissue hypoxia in endometrial cancer, seems to be associated with overexpression of Ob and ObR. Ob could exert autocrine effect to stimulate endometrial cancer progression. Thus the autocrine Ob loop should be taken into consideration as a novel potential target in endometrial cancer prevention and treatment.

Topics: Adult; Aged; Aged, 80 and over; Autocrine Communication; Disease Progression; Endometrial Neoplasms; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Middle Aged; Receptors, Cell Surface; Receptors, Leptin

Epidemiologic studies showed that leptin is closely related to the tumorigenesis of endometrial cancer, but the mechanism is unclear. As a mitogenic agent, leptin can promote the proliferation of many kinds of cells. This study was to explore the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in leptin promoting the proliferation of human endometrial cancer cell line Ishikawa.. The expression of leptin receptor OB-Rb in Ishikawa cells was detected by fluoroimmunoassay. Ishikawa cells were treated by leptin at various concentrations (0, 10, 50, 100, and 150 ng/ml) for different time (6, 12, and 24 h). Cell proliferation was examined by MTT assay. Meanwhile, the effect of PD98059, selective inhibitor of ERK1/2, on the proliferation of Ishikawa cells induced by leptin was also studied. Ishikawa cells were treated with 100 ng/ml leptin for different time (20, 40, and 60 min), then the levels of phosphorylated ERK1/2 (p-ERK1/2) and ERK1/2 were examined by Western blot.. Fluoroimmunoassay showed the presence of OB-Rb in Ishikawa cells. Leptin stimulated the proliferation of Ishikawa cells. This effect was maximal at 100 ng/ml after 24-hour treatment, and there was no significant difference between 100 ng/ml group and 150 ng/ml group (P=0.129). Blocking ERK1/2 phosphorylation by PD98059 significantly reduced the proliferation of Ishikawa cells stimulated by leptin. When treated with 100 ng/ml Leptin and 100 micromol/L PD98059 for 24 h, cell proliferation rate was (6.88+/-0.86)%. ERK1/2 phosphorylation was enhanced significantly in Ishikawa cells after treatment of 100 ng/ml leptin.. Leptin may promote the proliferation of endometrial cancer Ishikawa cells by activating ERK1/2 signaling pathway.

Topics: Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Flavonoids; Humans; Leptin; Mitogen-Activated Protein Kinase 3; Phosphorylation; Receptors, Leptin

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.

Topics: Cell Proliferation; Endometrial Neoplasms; Enzyme Activation; Female; Humans; Janus Kinase 1; Leptin; Mitogen-Activated Protein Kinase 1; Neoplasm Invasiveness; Obesity; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

Leptin and its receptor are the key players in the regulation of energy balance and body weight control. However, their roles in gynecological malignancies are mostly unclear. In this study, we analyzed the expression and possible involvement of leptin and the leptin receptor in the pathogenesis of endometrial cancer.. Radioimmunoassay was performed to analyze the serum leptin levels in the endometrial cancer patients, while RT-PCR, immunoblotting, and immunohistochemistry techniques were applied to study the expression of leptin receptor in the endometrioid-type endometrial cancer tissues. Furthermore, BrdU labeling followed by immunofluorescent analysis was used to analyze the effect of leptin receptor overexpression on endometrial cancer cell proliferation.. Serum leptin levels are elevated in endometrial cancer patients, but show no significant difference to those of normal controls when normalized by body mass index. On the other hand, lower expression levels of leptin receptor short form (Ob-Ra) were observed in most endometrial cancer tissues, especially in the poorly differentiated ones, and the forced expression of Ob-Ra in RL95-2 endometrial cancer cells prevented them from entering the S-phase.. In summary, our data demonstrates for the first time that the leptin receptor is aberrantly expressed in endometrial cancer tissues and is possibly involved in the pathogenesis of endometrial cancer.

Topics: Cell Division; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Middle Aged; Protein Isoforms; Radioimmunoassay; Receptors, Cell Surface; Receptors, Leptin; S Phase

Because leptin is a hormone associated with obesity and reproduction, we attempted to examine whether there is a relationship between leptin and endometrial cancer.. Cases were 84 women with histologically confirmed incident endometrial cancer, whereas controls were 84 women admitted to the same hospital for small surgical operations. The serum leptin levels were determined in fasting morning blood samples by using radioimmunoassay. The mean values of leptin levels among cases and controls were compared with simple t test, and the data were further analyzed using multiple logistic regression procedures.. The serum leptin levels were 36.7 +/- (SD) 25.7 ng/ml among cases and 26.9 +/- 19.8 ng/ml among controls (p = 0.006). After adjustment for known risk factors of endometrial cancer, components of the insulin-like growth factor system did not confound the association of leptin with endometrial cancer, but this association was eliminated, when the body mass index was adjusted for. Thus, the odds ratio for an increment of 1 SD of blood leptin was 1.52 (p = 0.03) before adjustment for body mass index, but only 1.13 (p = 0.62) after adjustment for it.. In a case-control study of incident endometrial cancer in Greece, we found evidence that leptin is strongly positively associated with endometrial cancer. It cannot be conclusively inferred, however, whether leptin elevation, as a consequence of obesity, plays a role in endometrial carcinogenesis or whether it is a simple correlate of obesity.

Topics: Body Mass Index; Case-Control Studies; Endometrial Neoplasms; Endometrium; Female; Greece; Humans; Insulin-Like Growth Factor I; Leptin; Logistic Models; Middle Aged; Obesity; Odds Ratio; Radioimmunoassay; Risk