Lymph node metastasis (LNM) is an important factor affecting endometrial cancer (EC) prognosis. Current controversy exists as to how to accurately assess the risk of lymphatic metastasis. Metabolic syndrome has been considered a risk factor for endometrial cancer, yet its effect on LNM remains elusive. We developed a nomogram integrating metabolic syndrome indicators with other crucial variables to predict lymph node metastasis in endometrial cancer.This study is based on patients diagnosed with EC in Peking University People's Hospital between January 2004 and December 2020. A total of 1076 patients diagnosed with EC and who underwent staging surgery were divided into training and validation cohorts according to the ratio of 2:1. Univariate and multivariate logistic regression analyses were used to determine the significant predictive factors.The prediction nomogram included MSR, positive peritoneal cytology, lymph vascular space invasion, endometrioid histological type, tumor size > = 2 cm, myometrial invasion > = 50%, cervical stromal invasion, and tumor grade. In the training group, the area under the curve (AUC) of the nomogram and Mayo criteria were 0.85 (95% CI: 0.81-0.90) and 0.77 (95% CI: 0.77-0.83), respectively (P < 0.01). In the validation group (N = 359), the AUC was 0.87 (95% CI: 0.82-0.93) and 0.80 (95% CI: 0.74-0.87) for the nomogram and the Mayo criteria, respectively (P = 0.01). Calibration plots revealed the satisfactory performance of the nomogram. Decision curve analysis showed a positive net benefit of this nomogram, which indicated clinical value.This model may promote risk stratification and individualized treatment, thus improving the prognosis.
The early predictive values of diagnostic markers for lymph node metastasis (LNM) in endometrial cancer (EC) are still unclear at present. The purpose of this study is to explore the relationship between serum calcium and LNM in EC.We identified all patients with EC who underwent surgery between January 2012 and December 2016. Patient characteristics and various preoperative clinicopathologic data were obtained from medical records and were reviewed retrospectively. These patients were divided into two groups according to the pathology of their lymph node. Logistic regression models analyzed the relationship between the ionized calcium and LNM of EC patients, while adjusting for the potential confounders.A total of 448 patients were assessed. Univariate analysis showed that ionized calcium, CA125 level, tumor grade, peritoneal cytology, FIGO stage, histological type, LVSI, and myometrial invasion were positively correlated with LNM (all P<0.05). The risk of LNM increased with the promotion of serum ionized calcium (P for trend <0.01). Ionized calcium level was significant before and after the adjustment of cofounders (unadjusted: OR=11.9, 95% CI: 4.8-29.6, P< 0.01; model I: OR=11.3, 95% CI: 4.5-28.8, P< 0.01; model II: OR=5.2, 95% CI: 1.6-17.2, P< 0.05). Additionally, the risk of ionized calcium was especially evident in patients whose age was older than 60, BMI<28 kg/m2, grade 3, negative peritoneal cytology and endometrioid endometrial adenocarcinoma.Ionized calcium level was highly associated with LNM in EC and acted as a potential biomarker in predicting the risk of LNM in EC.
Abstract Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patient EC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (Ishikawa HG ) mimicking hyperglycemia in patient EC+/dia+ . Subsequently, it is discovered that Ishikawa HG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of Ishikawa HG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits Ishikawa HG proliferation though Ishikawa HG is resistant to Met. Furthermore, a reduction‐sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06‐NPs) for drug delivery. It is found that in vitro JX06‐NPs have better inhibitory effect on the growth of Ishikawa HG as well as patient‐derived EC cells (PDC) than JX06. Additionally, it is found that JX06‐NPs can accumulate to the tumor of EC‐bearing mouse with diabetes (mice EC+/dia+ ) after intravenous injection, and JX06‐NPs combined Met can significantly inhibit tumor growth of mice EC+/dia+ . Taken together, the study demonstrates that the combination of JX06‐NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patients EC+/dia+ .
Transmembrane proteins are involved in the transportation of materials into and out of cells. The transmembrane protein (TMEM) family is a collection of poorly described transmembrane proteins that serve important roles in tumor development and progression. A number of TMEM proteins have been discovered. A newly discovered TMEM protein, TMEM206, transports ions across the membrane under physiological and pathological conditions, generating an acidic environment, which serves an important role in the microenvironment. However, the prognostic value and regulatory mechanisms of action of TMEM206 in tumors is unclear. The aim of the present study was to evaluate the prognostic value and regulation mechanisms of TMEM206 in tumors. Firstly, the expression of TMEM206 in tumors and normal tissues was assessed using the GEPIA and Oncomine databases and the results revealed that TMEM206 expression increased or decreased depending on the type of tumor. Subsequently, using the Human Protein Atlas and the Kaplan‑Meier plotter, the findings of the present study revealed that TMEM206 is related to the prognosis of hepatocellular carcinoma. In order to explore the mechanism of TMEM206 in promoting tumor progression, GEO and cBioPortal were used to determine genes that may be co‑expressed with TMEM206. MetaScape was used to identify the signaling pathways that TMEM206 may participate in. Finally, miRWalk, miRDB and TargetScan were used to identify miRNAs that may regulate the expression of TMEM206 and the findings revealed that 2 miRNA (hsa‑miR‑325 and hsa‑miR‑510‑5p) were involved. In conclusion, upregulation of TMEM206 is associated with poor prognosis in patients with hepatocellular carcinoma.
Abstract Background: Endometriosis is considered to be a complex gynecological disorder that affects the health and quality of life of affected women. The etiology and pathogenesis of endometriosis remain unclear, and few modifiable risk factors have been identified. It is generally believed that endometriosis is a chronic inflammatory disease, which can cause local immune disorders. And calcium homeostasis of the body is closely related to inflammation and immunity. Although observational studies have assessed the association between calcium homeostasis regulatory factor levels and endometriosis risk, the conclusions have been inconsistent. Therefore, the aim of this study was to explore the causal relationship between calcium homeostasis regulators and endometriosis risk using publicly available genome-wide association studies (GWAS) aggregated statistics. Methods: The Mendelian randomization (MR) analysis was performed using GWAS data, including calcium (N = 315,153), serum 25-Hydroxyvitamin D (25(OH)D) (N = 496,946), parathyroid hormone (PTH) (N = 3,301), endometriosis (N = 77,257), endometriosis of ovary (N = 72,200), endometriosis of rectovaginal septum and vagina (N = 70,329), endometriosis of intestine (N = 69,146), endometriosis of fallopian tube (N = 69,085), endometriosis of pelvic peritoneum (N = 71,922), endometriosis of uterus (N = 71,341), and Unspecified/other endometriosis (N = 70,404). Four levels of MR analysis were undertaken, starting with single univariate MR and multivariate MR to test the correlation between calcium homeostasis regulatory factors and endometriosis, followed by inverse MR to explore the effect of endometriosis on body calcium homeostasis. And further two-sample MR to probe the relationship between calcium levels and endometriosis subtypes. Cochran's Q test, MR-Egger intercept test, leave-one-out analysis and funnel plot were utilized for sensitivity analysis. Results: The two-sample MR analysis revealed a strong positive causal relationship between genetically predicted calcium levels and endometriosis risk (IVW: OR = 1.15, 95% CI: 1.02-1.29, p = 0.018). Notably, the results of MVMR analysis demonstrated that the positive correlation of calcium levels on endometriosis still held even after correction for 25(OH)D and PTH (OR = 1.14, 95% CI: 1.02-1.28, p = 0.026). After removing outliers using MR-PRESSO to ensure that horizontal pleiotropy was eliminated, MVMR analysis was performed again, and the causal association between calcium levels and endometriosis remained significant (OR = 1.13, 95% CI: 1.01-1.27, p = 0.033). The inverse MR analysis discovered a causal association between endometriosis and 25(OH)D (β = 0.01, 95% CI: 0.00-0.02, p = 0.007) and calcium (β = 0.02, 95% CI: 0.00-0.04, p = 0.035). The two-sample MR analysis we employed to further investigate that calcium levels were positively and causally associated only with endometriosis of uterus (IVW: OR = 1.23, 95% CI: 1.01-1.49, p = 0.038), with no suggestion of a causal relationship with the risk of other types of endometriosis subtypes. Conclusion：The comprehensive study of multiple types of MR provides genetic evidence for a causal relationship between calcium homeostasis and endometriosis risk, demonstrating that calcium levels are a risk factor for endometriosis. It also emphasizes the importance of monitoring calcium levels in patients suffering from endometriosis, which may provide dietary guidance for patients with endometriosis.
Endometrial cancer is one of the most common cancers of the female reproductive system. Although surgery, radiotherapy, chemotherapy and hormone therapy can significantly improve the survival of patients, the treatment of patients with very early lesions and a strong desire to retain reproductive function or late recurrence is still in the early stages. Metabolic syndrome (MS) is a clustering of at least three of the five following medical conditions: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Obesity, diabetes and hypertension often coexist in patients with endometrial cancer, which increases the risk of endometrial cancer, also known as the "triple syndrome of endometrial cancer". In recent years, epidemiological and clinical studies have found that MS associated with metabolic diseases is closely related to the incidence of endometrial cancer. However, the key molecular mechanisms underlying the induction of endometrial cancer by MS have not been elucidated to date. Characterizing the tumor metabolism microenvironment will be advantageous for achieving a comprehensive view of the molecular mechanism of metabolic syndrome associated with endometrial cancer and for providing a new target for the treatment of endometrial cancer. This review focuses on recent advances in determining the role of metabolic syndrome-related factors and mechanisms in the pathogenesis of endometrial cancer. We suggest that interfering with the tumor metabolic microenvironment-related molecular signals may inhibit the occurrence of endometrial cancer.
Calcium is present in serum mainly in filterable and bound forms, and Ca2+ is a major key to modulate signaling pathways that control oncogenesis and oncochannels associated with several types of cancer. However, the biological significance of serum calcium and its related mechanism with estrogen in endometrial cancer (EC) still remains elusive. This study aims to ascertain the relationship between serum calcium and clinicopathology in EC.Retrospective assessment of a total of 502 patients diagnosed with EC after surgery in Peking University People's Hospital from 2010 to 2018. Preoperative serum ionized calcium and the albumin corrected calcium was calculated in quartiles for various postoperative clinicopathological characteristics, logistic regression adjusted for potential confounders. Intracellular calcium homeostasis change induced by estrogen was detected by confocal analysis. Downstream pathways were analyzed by transcriptome and proteomics. Mitochondrial Ca2+ and ROS (reactive oxygen species) level was detected by confocal and flow cytometry. Lysosomal morphological and membrane changes were verified by confocal or Western blot assays.High level of albumin-corrected serum calcium was significantly correlated with EC clinicopathological characteristics progression include lymph vascular space invasion, lymph nodes metastasis, myometrial invasion, and cervical invasion. Calcium homeostasis regulated by estrogen in EC cells derived from extracellular calcium influx but not the release of the endoplasmic reticulum. Proteomic and bioinformatic analysis revealed the calcium influx might be involved in the regulation of autophagy and mitochondrial-related pathways. Mechanistic investigation demonstrated that calcium influx acted on the function of mitochondrial ROS and lysosomal activity.Our findings revealed that serum calcium level was significantly related to poor outcomes. The extracellular calcium influx induced by estrogen was targeted to mitochondrial ROS and lysosome activity, which should be oriented to improve EC therapeutic strategies.
Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells.A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage.We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression.Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.
OBJECTIVE Aimed to construct an immune-related risk signature and nomogram predicting endometrial cancer (EC) prognosis. METHODS An immune-related risk signature in EC was constructed using the least absolute shrinkage and selection operator regression analysis based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A nomogram integrating the immune-related genes and the clinicopathological characteristics was established and validated using the Kaplan-Meier survival curve and receiver operating characteristic (ROC) curve to predict the overall survival (OS) of EC patients. The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) R tool was used to explore the immune and stromal scores. RESULTS CCL17, CTLA4, GPI, HDGF, HFE2, ICOS, IFNG, IL21R, KAL1, NR3C1, S100A2, and S100A9 were used in developing an immune-related risk signature evaluation model. The Kaplan-Meier curve indicated that patients in the low-risk group had better OS (p<0.001). The area under the ROC curve (AUC) values of this model were 0.737, 0.764, and 0.782 for the 3-, 5-, and 7-year OS, respectively. A nomogram integrating the immune-related risk model and clinical features could accurately predict the OS (AUC=0.772, 0.786, and 0.817 at 3-, 5-, and 7-year OS, respectively). The 4 immune cell scores were lower in the high-risk group. Forkhead box P3 (FOXP3) and basic leucine zipper ATF-like transcription factor (BATF) showed a potential significant role in the immune-related risk signature. CONCLUSION Twelve immune-related genes signature and nomogram for assessing the OS of patients with EC had a good practical value.
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