Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.

Microsatellite Instability as a Maker of Prognosis: a Systematic Review and Meta-analysis of Endometrioid Endometrial Cancer Survival Data

Introduction To investigate whether microsatellite instability (MSI) is an important prognostic biomarker for endometrioid endometrial cancer (EEC).Methods The PubMed, EMBASE and the Cochrane Cooperative Library databases were searched from inception to July 2021. Overall survival, disease-free survival, progression-free survival, EEC-specific survival, recurrence-free survival and the recurrence rate were pooled to analyze the correlation between MSI and EEC. In addition, Egger’s regression analysis and Begg’s test were used to detect publication bias.Results 17 studies met the inclusion criteria and were included in our meta-analysis with a sample size of 4723, and the included patients with endometrioid cancer (EC) all were EEC. The pooled hazard ratios (HR) in patients with EEC shown that MSI was significantly associated with shorter overall survival [HR=1.37, 95% confidence interval (CI) (1.00-1.86), p=0.048, I2=60.6%], shorter disease-free survival [HR=1.99, 95% CI (1.31-3.01), p=0.000, I2=67.2%], shorter EEC-specific survival [HR=2.07, 95% CI (1.35-3.18), p=0.001, I2=31.6%] and a higher recurrence rate [Odds ratios (OR)=2.72, 95% CI (1.56-4.76), p=0.000, I2=0.0%]. In the early-stage EEC subgroup, MSI was significantly associated with shorter overall survival [HR=1.47, 95% CI (1.11-1.95), p=0.07], shorter disease-free survival [HR=4.17, 95% CI (2.37-7.41), p=0.000], and shorter progression-free survival [HR=2.41, 95% CI (1.05-5.54), p=0.039]. No significant heterogeneity was observed in overall survival (I2=20.9%), disease-free survival (I2=0.0%), or progression-free survival (I2=0.0%) in patients with early-stage EEC. Meanwhile, publication bias was not observed, and the p-value for Egger’s test of overall survival, disease-free survival, and EEC-specific survival were p=0.131, p=0.068 and p=0.987, respectively.Conclusion MSI is likely an important biomarker for poor prognosis in patients with EEC, and this correlation is even more certain in patients with early-stage EEC.

SPTBN2 regulated by miR-424-5p promotes endometrial cancer progression via CLDN4/PI3K/AKT axis

Endometrioid Endometrial Cancer (EEC) is the main subtype of endometrial cancer. In our study, we demonstrated that SPTBN2 was significantly overexpressed in EEC tissues. Upregulated SPTBN2 expression was positively associated with poor prognosis. In addition, we testified that SPTBN2 knockdown significantly inhibited the proliferation, migration, and invasion of EEC cells. Moreover, we found SPTBN2 could interact with CLDN4 to promote endometrial cancer metastasis via PI3K/AKT pathway. Then we further demonstrated that CLDN4 is upregulated in EEC and promotes EEC metastasis. CLDN4 overexpression could partially reversed the decrease in cell migration and invasion caused by SPTBN2 downregulation. In addition, we confirmed that SPTBN2 was a target of miR-424-5p, which plays a tumor suppressor in endometrial cancer. Rescue experiments showed that inhibition of SPTBN2 could partially reverse the effect of miR-424-5p in EEC. In conclusion, we demonstrated that by acting as a significant target of miR-424-5p, SPTBN2 could interact with CLDN4 to promote endometrial cancer metastasis via PI3K/AKT pathway in EEC. Our study revealed the prognostic and metastatic effects of SPTBN2 in EEC, suggesting that SPTBN2 could serve as a prognostic biomarker and a target for metastasis therapy.

Evaluation of the Differences in the Expression of Biogenic Amine-Related mRNAs and Proteins in Endometrioid Endometrial Cancer

Biogenic amines, such as adrenaline, noradrenaline, histamine, dopamine, and serotonin are important neurotransmitters that also regulate cell viability. Their detection and analysis are helpful in the diagnosis of many diseases, including cancer. The aim of this study was to determine the expression profile of the biogenic amine-related genes and proteins in endometrioid endometrial cancer compared to the control group. The material consisted of endometrial tissue samples and whole blood collected from 30 endometrioid endometrial cancer patients and 30 cancer-free patients. The gene expression was determined by the mRNA microarrays and validated by qRT-PCR. Protein levels were determined in the serum by the enzyme-linked immunosorbent assay (ELISA). Overexpression of histamine H1–H3 receptors and early growth response 1 and silencing of calmodulin, the histamine H4 receptor, and the dopamine D5 receptor have been reported in endometrioid endometrial cancer. The obtained results indicate disturbances in the signaling activated by histamine and dopamine receptors, which could potentially contribute to the progression of endometrioid endometrial cancer.

Long-Term Survival and Clinicopathological Implications of DNA Mismatch Repair Status in Endometrioid Endometrial Cancers in Hong Kong Chinese Women

To investigate the role of DNA mismatch repair status (MMR) in survival of endometrioid endometrial cancer in Hong Kong Chinese women and its correlation to clinical prognostic factors, 238 patients with endometrioid endometrial cancer were included. Tumor MMR status was evaluated by immunohistochemistry. Clinical characteristics and survival were determined. Association of MMR with survival and clinicopathological parameters were assessed. MMR deficiency (dMMR) was found in 43 cases (16.5%). dMMR was associated with poor prognostic factors including older age, higher stage, higher grade, larger tumor size and more radiotherapy usage. Long-term survival was worse in dMMR compared to the MMR proficient group. The dMMR group had more deaths, shorter disease-specific survival (DSS), shorter disease-free survival (DFS), less 10-year DSS, less 10-year DFS, and more recurrence. The 5-year DSS and 5-year DFS in the dMMR group only showed a trend of worse survival but did not reach statistical significance. In conclusion, dMMR is present in a significant number of endometrioid endometrial cancers patients and is associated with poorer clinicopathological factors and survival parameters in the long run. dMMR should be considered in the risk stratification of endometrial cancer to guide adjuvant therapy and individualisation for longer follow up plan.