LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination.

Endometrial cancer (EC) cells exhibit abnormal glucose metabolism, characterized by increased aerobic glycolysis and decreased oxidative phosphorylation. Targeting cellular glucose metabolism in these cells could be an effective therapeutic approach for EC. This study aimed to assess the roles of LIN28B, PCAT5, and IGF2BP3 in the glucose metabolism, proliferation, migration, and invasion of EC cells. LIN28B highly expressed in EC, binds and stabilizes PCAT5. PCAT5, overexpressed in EC, and its 1485-2288nt region can bind to the KH1-2 domain of IGF2BP3 to prevent MKRN2 from binding to the K294 ubiquitination site of IGF2BP3, thus stabilizing IGF2BP3. Finally, IGF2BP3 promotes the aerobic glycolysis, proliferation, migration and invasion of EC cells by stabilizing the key enzymes of glucose metabolism HK2 and PKM2. Taken together, our data reveal that the LIN28B/PCAT5/IGF2BP3 axis is critical for glucose reprogramming and malignant biological behavior in EC cells. Therefore, targeting this axis may contribute to the development of a novel therapeutic strategy for EC metabolism.

Proteomic characterization of epithelial ovarian cancer delineates molecular signatures and therapeutic targets in distinct histological subtypes.

Clear cell carcinoma (CCC), endometrioid carcinoma (EC), and serous carcinoma (SC) are the major histological subtypes of epithelial ovarian cancer (EOC), whose differences in carcinogenesis are still unclear. Here, we undertake comprehensive proteomic profiling of 80 CCC, 79 EC, 80 SC, and 30 control samples. Our analysis reveals the prognostic or diagnostic value of dysregulated proteins and phosphorylation sites in important pathways. Moreover, protein co-expression network not only provides comprehensive view of biological features of each histological subtype, but also indicates potential prognostic biomarkers and progression landmarks. Notably, EOC have strong inter-tumor heterogeneity, with significantly different clinical characteristics, proteomic patterns and signaling pathway disorders in CCC, EC, and SC. Finally, we infer MPP7 protein as potential therapeutic target for SC, whose biological functions are confirmed in SC cells. Our proteomic cohort provides valuable resources for understanding molecular mechanisms and developing treatment strategies of distinct histological subtypes.

Endoscopic treatment and management of rectal neuroendocrine tumors less than 10 mm in diameter.

Rectal neuroendocrine tumors (rNETs) measuring less than 10 mm in diameter are defined as small rNETs. Due to the low risk of distant invasion and metastasis, endoscopic treatments, including modified endoscopic mucosal resection, endoscopic submucosal dissection, and other transanal surgical procedures, are effective. This review article proposes a follow-up plan according to the size and histopathology of the tumor after operation.

T-Cell Mineralocorticoid Receptor Deficiency Attenuates Pathologic Ventricular Remodelling After Myocardial Infarction.

BACKGROUND: Mineralocorticoid receptor (MR) antagonists have been widely used to treat heart failure (HF). Studies have shown that MR in T cells plays important roles in hypertension and myocardial hypertrophy. However, the function of T-cell MR in myocardial infarction (MI) has not been elucidated. METHODS: In this study, we used T-cell MR knockout (TMRKO) mouse to investigate the effects of T-cell MR deficiency on MI and to explore the underlying mechanisms. Echocardiography and tissue staining were used to assess cardiac function, fibrosis, and myocardial apoptosis after MI. Flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect immune cell infiltration and inflammation. RESULTS: T-cell MR deficiency significantly improved cardiac function, promoted myocardial repair, and inhibited myocardial apoptosis, fibrosis, and inflammation after MI. Luminex assays revealed that TMRKO mice had significantly lower levels of interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in serum and infarcted myocardium than littermate control mice. In cultured splenic T cells, MR deficiency suppressed IL-6 expression, whereas MR overexpression enhanced IL-6 expression. Chromatin immunoprecipitation (ChIP) assay demonstrated that MR bound to the MR response element on the promoter of IL-6 gene. Finally, T-cell MR deficiency significantly suppressed accumulation of macrophages in infarcted myocardium and differentiation of proinflammatory macrophages, thereby alleviating the consequences of MI. CONCLUSIONS: T-cell MR deficiency improved pathologic ventricular remodelling after MI, likely through inhibition of accumulation and differentiation of proinflammatory macrophages. At the molecular level, MR may work through IFN-γ and IL-6 in T cells to exert functions in MI.

Macrophage Nuclear Receptor Corepressor 1 Deficiency Protects Against Ischemic Stroke in Mice.

Microglia/macrophage activation plays an essential role in Ischemic stroke (IS). Nuclear receptor corepressor 1 (NCoR1) has been identified as a vital regulator in macrophages. The present study aims to explore the functions of macrophage NCoR1 in IS. Macrophage NCoR1 knockout (MNKO) mice and littermate control mice were subjected to middle cerebral artery occlusion (MCAO). Our data showed that macrophage NCoR1 deficiency significantly reduced the infarct size and infarct volume as well as brain edema after MCAO. Additionally, MNKO induced less microglia/macrophage infiltration and activation, neuroinflammation, apoptosis of neuronal cells, and BBB disruption in brains after IS. Mechanistic studies revealed that NCoR1 interacted with LXRß in microglia and MNKO impaired the activation of the Nuclear factor-κB signaling pathway in brains after IS. Our data demonstrated that macrophage NCoR1 deficiency inhibited microglia/macrophage activation and protected against IS. Targeting NCoR1 in microglia/macrophage may be a potential approach for IS treatment.

CDKN2B-AS1 Promotes Malignancy as a Novel Prognosis-Related Molecular Marker in the Endometrial Cancer Immune Microenvironment.

The prognosis of patients with endometrial cancer (EC) is closely associated with immune cell infiltration. Although abnormal long non-coding RNA (lncRNA) expression is also linked to poor prognosis in patients with EC, the function and action mechanism of immune infiltration-related lncRNAs underlying the occurrence and development of EC remains unclear. In this study, we analyzed lncRNA expression using The Cancer Genome Atlas and clinical data and identified six lncRNAs as prognostic markers for EC, all of which are associated with the infiltration of immune cell subtypes, as illustrated by ImmLnc database and ssGSEA analysis. Real-time quantitative polymerase chain reaction showed that CDKN2B-AS1 was significantly overexpressed in EC, whereas its knockdown inhibited the proliferation and invasion of EC cells and the in vivo growth of transplanted tumors in nude mice. Finally, we constructed a competing endogenous RNA regulatory network and conducted Gene Ontology enrichment analysis to elucidate the potential molecular mechanism underlying CDKN2B-AS1 function. Overall, we identified molecular targets associated with immune infiltration and prognosis and provide new insights into the development of molecular therapies and treatment strategies against EC.

Immune infiltration-related N6-methyladenosine RNA methylation regulators influence the malignancy and prognosis of endometrial cancer.

N6-methyladenosine (m6A) RNA methylation is associated with malignant tumor progression and is modulated by various m6A RNA methylation regulator proteins. However, its role in endometrial cancer is unclear. In this work, we analyzed sequence, copy number variation, and clinical data obtained from the TCGA database. Expression was validated using real-time quantitative polymerase chain reaction and immunohistochemistry. Changes in m6A RNA methylation regulators were closely related to the clinicopathological stage and prognosis of endometrial cancer. In particular, ZC3H13, YTHDC1, and METTL14 were identified as potential markers for endometrial cancer diagnosis and prognosis. The TIMER algorithm indicated that immune cell infiltration correlated with changes in ZC3H13, YTHDC1, and METTL14 expression. Meanwhile, ZC3H13 or YTHDC1 knockdown promoted the proliferation and invasion of endometrial cancer cells. Through gene enrichment analysis, we constructed a regulatory network in order to explore the potential molecular mechanism involving ZC3H13, YTHDC1, and METTL14. Virtual screening predicted interactions of potential therapeutic compounds with METTL14 and YTHDC1. These findings advance the understanding of RNA epigenetic modifications in endometrial cancer while identifying m6A regulators associated with immune infiltration, prognosis, and potential treatment strategies.

lncRNA MIR210HG promotes the progression of endometrial cancer by sponging miR-337-3p/137 via the HMGA2-TGF-ß/Wnt pathway.

Epithelial-mesenchymal transition (EMT) promotes tumorigenesis and metastasis and increases tumor tolerance to treatment intervention. Abnormal activation of transforming growth factor ß (TGF-ß) and Wnt pathway induces EMT. Long non-coding RNAs (lncRNAs) significantly influence EMT regulation. Herein, we show that MIR210HG is overexpressed in endometrial cancer tissues, which is associated with poor prognosis. MIR210HG silencing significantly inhibited proliferation, migration, invasion, and EMT phenotype formation in vitro as well as tumorigenesis in vivo. Mechanistically, bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, and luciferase assays showed that MIR210HG acts as a molecular sponge of miR-337-3p and miR-137 to regulate the expression of HMGA2. Additionally, MIR210HG overexpression significantly enriched the Wnt/ß-catenin and TGF-ß/Smad3 signaling pathway genes, while MIR210HG or HMGA2 knockdown suppressed the Wnt/ß-catenin and TGF-ß/Smad3 signaling pathway. Our findings on the MIR210HG-miR-337-3p/137-HMGA2 axis illustrate its potential as a target for endometrial cancer therapeutic development.

Withanolides isolated from Tubocapsicum anomalum and their antiproliferative activity.

Seven undescribed withanolides (1-7) and six artificial withanolides (8-13), along with 20 known compounds (14-33) were isolated from the aerial parts of Tubocapsicum anomalum. Their structures were confirmed by comprehensive spectroscopic analyses. The absolute configuration of compound 1 was defined by single-crystal X-ray crystallography. All isolates were evaluated for their antiproliferative effects against five human tumor cell lines (Hep3B, MDA-MB-231, SW480, HCT116 and A549), among which compound 24 (tubocapsanolide A) exhibited the highest activities against the MDA-MB-231 cells with an IC50 value of 1.89 ± 1.03 µM. Further studies showed that 24 exhibited significant damage to mitochondria in MDA-MB-231 cells, including excess reactive oxygen species, decreased mitochondrial membrane potential, and apoptosis initiation. In addition, compound 24 also inhibited cell migration. These findings show that tubocapsanolide A may be a promising molecule for triple-negative breast cancer treatment and merit further evaluation.

Adherence to Cancer Prevention Guidelines and Endometrial Cancer Risk: Evidence from a Systematic Review and Dose-Response Meta-analysis of Prospective Studies.

PURPOSE: The evidence of adherence to cancer prevention guidelines and endometrial cancer (EC) risk has been limited and controversial. This study summarizes and quantifies the relationship between adherence to cancer prevention guidelines and EC risk. MATERIALS AND METHODS: The online databases PubMed, Web of Science, and EMBASE were searched for relevant publications up to June 2, 2020. This study had been registered at PROSPERO. The registration number is CRD42020149966. Study quality evaluation was performed based on the Newcastle-Ottawa Scale. The I2 statistic was used to estimate heterogeneity among studies. Egger's and Begg's tests assessed potential publication bias. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationship between adherence to cancer prevention guidelines score was assigned to participants by summarizing individual scores for each lifestyle-related factor. The scores ranged from least healthy (0) to most healthy (20) and the EC risk was calculated using a randomeffects model. RESULTS: Five prospective studies (four cohort studies and one case­cohort study) consisted of 4,470 EC cases, where 597,047 participants were included. Four studies had a low bias risk and one study had a high bias risk. Summary EC HR for the highest vs. lowest score of adherence to cancer prevention guidelines was 0.54 (95% CI, 0.40 to 0.73) and had a high heterogeneity (I2=86.1%). For the dose-response analysis, an increment of 1 significantly reduced the risk of EC by 6%. No significant publication bias was detected. CONCLUSION: This study suggested that adherence to cancer prevention guidelines was negatively related to EC risk.

Identification of novel prognosis-related genes in the endometrial cancer immune microenvironment.

The incidence of endometrial cancer is increasing each year, and treatment effects are poor for patients with advanced and specific subtypes. Exploring immune infiltration-related factors in endometrial cancer can aid in the prognosis of patients and provide new immunotherapy targets. We downloaded immune metagene and functional data of patients with different subtypes of endometrial cancer from The Cancer Genome Atlas database and selected the lymphocyte-specific kinase (LCK) metagene as a representative genetic marker of the immune microenvironment in endometrial cancer. The results showed that LCK metagene expression is related to the prognosis of patients with endometrioid endometrial adenocarcinoma subtypes and highly correlated with the PTEN and PIK3CA mutational status. A search for LCK-related modules returned seven independent genetic predictors of survival in patients with endometrial cancer. The TIMER algorithm showed that the expression of these seven genes was positively correlated with the infiltration levels of six types of immune cells. The diagnostic value of these markers was validated using real-time quantitative PCR and immunohistochemical methods. Our results identified CD74, HLA-DRB5, CD52, HLA-DPB1 and HLA-DRB1 as possible valuable genetic markers for the diagnosis and prognosis of endometrial cancer and provided a theoretical basis for immunotherapy targets for its clinical treatment.

Choriocarcinoma with lumbar muscle metastases: A case report.

BACKGROUND: Choriocarcinoma is a highly malignant trophoblastic tumor that presents with early symptoms similar to those of an ectopic pregnancy. Here we present a patient with suspected ectopic pregnancy diagnosed by laparoscopic surgery in our hospital. The patient was found to have choriocarcinoma that had metastasized to the lumbar muscle and presented with symptoms similar to those of an ectopic pregnancy. CASE SUMMARY: The patient was a 34-year-old female who complained of amenorrhea lasting 53 d, 7 d of right lower back pain, and 3 d of right lower abdominal pain. Transvaginal ultrasonography revealed the absence of a gestational sac in the uterus and a mass in the left adnexa. After 6 d of re-examination, ultrasound and computed tomography (CT) examination were performed on the mass located in the left adnexa area. We also noted that the patient's serum ß-human chorionic gonadotropin (hCG) level was increased. Considering an ectopic pregnancy, we performed a laparoscopy and hysteroscopy. During the operation, a left ovarian mixed echogenic mass approximately 2.5 cm × 2.0 cm with no villous tissue was found. Postoperative levels of serum hCG continued to increase. Lung CT examination showed lung nodules. Both CT and magnetic resonance imaging showed a mixed echogenic mass in the lumbar muscle. Considering lumbar metastasis of choriocarcinoma, six courses of cisplatin, dactinomycin, and etoposide chemotherapy were given after surgery. The patient's serum ß-hCG level decreased to normal and the mixed echogenic mass in the lumbar muscle decreased in size after the fifth course of chemotherapy. All symptoms subsequently disappeared after treatment. CONCLUSION: In summary, lumbar metastasis from choriocarcinoma is extremely rare. Appropriate chemotherapy can successfully treat these metastasized tumors.

Identification of novel cell glycolysis related gene signature predicting survival in patients with endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is one of the three major gynecological malignancies. Numerous biomarkers that may be associated with survival and prognosis have been identified through database mining in previous studies. However, the predictive ability of single-gene biomarkers is not sufficiently specific. Genetic signatures may be an improved option for prediction. This study aimed to explore data from The Cancer Genome Atlas (TCGA) to identify a new genetic signature for predicting the prognosis of EC. METHODS: mRNA expression profiling was performed in a group of patients with EC (n = 548) from TCGA. Gene set enrichment analysis was performed to identify gene sets that were significantly different between EC tissues and normal tissues. Cox proportional hazards regression models were used to identify genes significantly associated with overall survival. Quantitative real-time-PCR was used to verify the reliability of the expression of selected mRNAs. Subsequent multivariate Cox regression analysis was used to establish a prognostic risk parameter formula. Kaplan-Meier survival estimates and the log-rank test were used to validate the significance of risk parameters for prognosis prediction. RESULT: Nine genes associated with glycolysis (CLDN9, B4GALT1, GMPPB, B4GALT4, AK4, CHST6, PC, GPC1, and SRD5A3) were found to be significantly related to overall survival. The results of mRNA expression analysis by PCR were consistent with those of bioinformatics analysis. Based on the nine-gene signature, the 548 patients with EC were divided into high/low-risk subgroups. The prognostic ability of the nine-gene signature was not affected by other factors. CONCLUSION: A nine-gene signature associated with cellular glycolysis for predicting the survival of patients with EC was developed. The findings provide insight into the mechanisms of cellular glycolysis and identification of patients with poor prognosis in EC.

Global, Regional, and National Burden of Endometrial Cancer, 1990-2017: Results From the Global Burden of Disease Study, 2017.

Endometrial cancer (EC) is the most common malignancy affecting women in developed countries. Recently, the EC disease burden has changed; therefore, the Global Burden of Disease (GBD) 2017 was used to comprehensively analyze the global, regional, and national burden of EC between 1990 and 2017. General GBD cancer estimation methods were used with the data input from vital registration systems and cancer registries. Annual percent changes were calculated to quantify the trends of EC burden estimates during the study period. Furthermore, the sociodemographic index (SDI) was used to assess the relationship between the EC burden estimates and development level. From 1990 to 2017, the age-standardized incidence and prevalence rate of EC increased globally by 0.58 and 0.89% per year, respectively. In contrast, the age-standardized death rate and disability-adjusted-life years (DALYs) decreased by 1.19 and 1.21% per year, respectively. Increasing trends in both the incidence and prevalence were observed in all SDI quintiles, except for the low SDI quintiles, whereas decreasing trends were observed in all SDI quintiles for mortality and DALYs. Additionally, a non-linear association existed for the level of mortality rate, DALYs, and SDI. Of note, there was a strong positive association between a high body mass index and DALYs across all SDI quintiles. In conclusion, EC incidence and prevalence rates are growing globally, whereas the death rate and DALYs decreased between 1990 and 2017. Greater efforts, particularly detailed prevention strategies for reducing obesity, should be performed to reverse this phenomenon.

Hyperhomocysteinemia in polycystic ovary syndrome: decreased betaine-homocysteine methyltransferase and cystathionine ß-synthase-mediated homocysteine metabolism.

RESEARCH QUESTION: What are the metabolic characteristics of homocysteine in polycystic ovary syndrome (PCOS)? DESIGN: Homocysteine concentrations were determined in serum samples from non-obese and obese control subjects and PCOS patients. Homocysteine metabolism was studied in a rat model of PCOS established using dehydroepiandrosterone (DHEA) or DHEA in combination with a high-fat diet (HFD). RESULTS: It was shown that (i) serum homocysteine concentrations were greater in PCOS patients than in control subjects in the obese group (P < 0.05) and serum homocysteine concentrations were significantly higher in the obese group than in the non-obese group, regardless of PCOS status (both P < 0.05); (ii) serum homocysteine concentrations were significantly increased in DHEA + HFD-induced rats compared with controls (P < 0.05); (iii) when compared with the control group, mRNA concentrations of homocysteine metabolic enzymes Bhmt and Cbs were significantly reduced in the liver tissues of DHEA + HFD-induced rats (both P < 0.0001); (iv) when compared with the control group, there was a significant decrease in the methylation concentrations of the Cbs (P < 0.05) and Bhmt (P < 0.05 and P < 0.0001) promoter in the DHEA + HFD group. The methylation patterns, together with previous data, indicate that hypomethylated promoter-mediated transcriptional activation of Bhmt and Cbs might be a defence mechanism against PCOS-related hyperhomocysteinemia. CONCLUSIONS: These findings indicate that decreased liver Bhmt and Cbs-mediated homocysteine metabolism might have a role in hyperhomocysteinemia in PCOS and provides further evidence for a potential role of decreased liver function in PCOS.

miR-302a-5p/367-3p-HMGA2 axis regulates malignant processes during endometrial cancer development.

BACKGROUND: Metastasis is one of the main reasons for treatment failure in endometrial cancer. Notably, high mobility group AT-hook 2 (HMGA2) has been recognized as a driving factor of tumour metastasis. microRNAs (miRNAs) are powerful posttranscriptional regulators of HMGA2. METHODS: The binding sites of miR-302a-5p and miR-367-3p on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. The expression levels of miR-302a-5p and miR-367-3p were detected using quantitative real-time PCR and in situ hybridization. Western blotting and immunohistochemistry were used to detect the levels of HMGA2 and epithelial-mesenchymal transition pathway-related proteins. Co-immunoprecipitation was used to detect protein interactions. The roles of miR-302a-5p and miR-367-3p in the regulation of HMGA2 during the progression of endometrial cancer were investigated using both in vitro and in vivo assays. RESULTS: In the present study, high HMGA2 expression was correlated with poor clinical outcomes in endometrial cancer. The binding sites of miRNAs on HMGA2 mRNA were identified using bioinformatics prediction software and were validated via luciferase assay. In the endometrial cancer cell lines Ishikawa and HEC-1A, the overexpression of miR-302a-5p/367-3p significantly inhibited the expression of HMGA2 mRNA. In endometrial cancer tissues, we showed that miR-302a-5p and miR-367-3p were significantly downregulated and thus inversely correlated with HMGA2. The miR-302a-5p and miR-367-3p expression levels were closely correlated with FIGO stage and lymph node metastasis. High expression of miR-302a-5p/367-3p was correlated with high survival rates in endometrial cancer. In addition, miR-302a-5p/367-3p suppressed the malignant behaviour of endometrial carcinoma cells via the inhibition of HMGA2 expression. CONCLUSION: Our findings indicate that miR-302a-5p/367-3p-mediated expression of HMGA2 regulates the malignant behaviour of endometrial carcinoma cells, which suggests that the miR-302a-5p/367-3p-HMGA2 axis may be a predictive biomarker of endometrial cancer metastasis and patient survival and a potential therapeutic target in metastatic endometrial cancer.

Preliminary identification of endometrial cancer stem cells in vitro and in vivo.

Stem cells play a critical role in endometrial cancer progression. However, the current methodologies used to isolate endometrial cancer stem cells (ECSCs) remain unsatisfactory. The ECSCs were isolated by serumfree suspension cultivation. The stem cells-related genes CD44, CD133, Oct4, Sox2 and Nanog were analyzed, and the biological behaviour of ECSCs was evaluated in vitro and vivo. The results suggest that (i) serumfree suspension cultivation is non-toxic and a convenient way for isolating the ECSCs, and is not limited to specific surface markers; (ii) Ishikawa cells can be used as an effective source of ECSCs, and the obtained ECSCs expressing the pluripotent stem cells markers CD44, CD133, Oct4, Sox2, and Nanog; (iii) ECSCs originated from Ishikawa cells showed an increased ability to invasion and metastasis in vitro, and exhibited a high proliferative capacity and pluripotency in vivo and vitro. These findings indicate that serumfree suspension cultivation is an effective method for isolating ECSCs from Ishikawa cells, and the obtained ECSCs are tumorigenic and display stem cell-like properties.

Effects of receptor for advanced glycation endproducts on microvessel formation in endometrial cancer.

BACKGROUND: The receptor for advanced glycation endproducts (RAGE) and microvascular status both play a critical role in cancer progression. However, the crosstalk between RAGE and microvascular formation in endometrial cancer remains largely unknown. METHODS: RAGE expression and microvessel density were examined in 20 cases of normal endometrial tissue, 37 cases of well-differentiated endometrial cancer tissue, and 35 cases of poorly-differentiated endometrial cancer tissue. Regression analysis was used to examine the relationship between RAGE and microvessel density. The knockdown of RAGE was achieved using a small interfering RNA in HEC-1A endometrial cancer cells. A xenografted tumour model was used to evaluate RAGE-mediated microvascular formation and proliferation of endometrial cancer cells. RESULTS: It was shown that (i) RAGE expression gradually increased in normal endometrium, well-differentiated endometrial cancer, and poorly-differentiated endometrial cancer, respectively; (ii) a positive correlation existed between RAGE and microvessel density in human endometrial cancer samples; (iii) RAGE knockdown was effective in decreasing microvessel formation in xenografted tumour models; and (iv) RAGE knockdown can significantly inhibit the proliferation of endometrial cancer cells in vivo. CONCLUSIONS: These results indicate that RAGE may be a potential trigger in microvascular formation and proliferation in the development of endometrial cancer.

Parity and endometrial cancer risk: a meta-analysis of epidemiological studies.

The association between parity and endometrial cancer risk is inconsistent from observational studies. We aimed to quantitatively assess the relationship by summarizing all relevant epidemiological studies. PubMed (MEDLINE), Embase and Scopus were searched up to February 2015 for eligible case-control studies and prospective studies. Random-effects model was used to pool risk estimations. Ten prospective studies, 35 case-control studies and 1 pooled analysis of 10 cohort and 14 case-control studies including 69681 patients were identified. Pooled analysis revealed that there was a significant inverse association between parity and risk of endometrial cancer (relative risk (RR) for parous versus nulliparous: 0.69, 95% confidence interval (CI) 0.65-0.74; I(2) = 76.9%). By evaluating the number of parity, we identified that parity number of 1, 2 or 3 versus nulliparous demonstrated significant negative association (RR = 0.73, 95% CI 0.64-0.84, I(2) = 88.3%; RR = 0.62, 95% CI 0.53-0.74, I(2) = 92.1%; and RR = 0.68, 95% CI 0.65-0.70, I(2) = 20.0% respectively). The dose-response analysis suggested a nonlinear relationship between the number of parity and endometrial cancer risk. The RR decreased when the number of parity increased. This meta-analysis suggests that parity may be associated with a decreased risk of endometrial cancer. Further studies are warranted to replicate our findings.

Age at menarche and endometrial cancer risk: a dose-response meta-analysis of prospective studies.

Evidence between age at menarche and endometrial cancer risk have been controversial. Therefore, we conducted a meta-analysis of prospective studies to analyze the aforementioned association. Relevant studies were identified by searching PubMed and EMBASE databases until the end of June 2015. A random-effects model was used to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) for associations between menarcheal age and endometrial cancer risk. Our meta-analysis included eight prospective studies involving 4553 subjects with endometrial cancer. The summarized RRs of endometrial cancer for menarcheal age were 0.68 (95%CI = 0.58-0.81, I(2) = 41.9%, P = 0.099, n = 8) when comparing women with oldest category of menarcheal age with women with youngest category of menarcheal age. Notably, there was an 4% reduction in risk for per 2 years delay in menarcheal age (summarized RR = 0.96; 95%CI = 0.94-0.98, I(2) = 45.7%, P = 0.101, n = 6). Additionally, significant inverse associations were consistent within all stratified analyses. There was no evidence of publication bias or significant heterogeneity between subgroups detected by meta-regression analyses. Our findings support the hypothesis that late menarcheal age is inversely associated with endometrial cancer risk. Further larger prospective or pooled studies are warranted to fully adjust for potential confounders and distinguish whether the associations differ by histological subtypes of endometrial cancer.