E74-Like Factor 3 Promotes Endometrial Cancer Cell Proliferation, Migration and Invasion via Regulating Mucin 1/Hypoxia-Inducible Factor 1α Pathway

High expression of E74-like factor 3 (ELF3) has been reported in type 1 endometrial cancer (EC). Bioinformatics analysis predicted a positive correlation with ELF3 and mucin 1 (MUC1)/hypoxiainducible factor 1α (HIF-1α), a previously identified cancer-promoting pathway. This study focused on the MUC1/HIF-1α-involved action mechanism of ELF3 in EC. ELF3 expression in EC cell lines was measured by RT-qPCR and western blot analysis. Following the expression of ELF3 was silent, cell proliferation was examined using CCK-8 and colony formation assay, cell migration and invasion were observed using wound healing and transwell assays. The effect of ELF1 silencing on MUC1/HIF-1α expression was detected by western blot. Rescue experiments incorporating pcDNA3.1(+)/MUC1 explored the interaction between ELF3 and MUC1/HIF-1α in EC cell proliferation, migration and invasion. ELF3 was found to be expressed at a high level in EC cell lines, and the silencing of it effectively inhibited EC cell proliferation. Moreover, ELF silencing also inhibited the migration and invasion of EC cells. Consistent with the database prediction, a positive correlation between ELF3 and MUC1/HIF-1α was observed. More importantly, MUC1 overexpression abated the promotive effect of ELF3 silencing on EC cell proliferation, migration and invasion. ELF3 promotes EC cell proliferation, migration and invasion by regulating MUC1/HIF-1α pathway. Thus, ELF3 as well as MUC1/HIF-1α pathway may be particle targets in the treatment of EC.

Association Between Hormone Replacement Therapy and Development of Endometrial Cancer: Results From a Prospective US Cohort Study

Although hormone replacement therapy (HRT) use is associated with elevated endometrial cancer(EC) risk, little evidence assesses potential effect-modifiers on HRT-related EC in a long-term follow-up. In this large-scale longitudinal cohort study, we tried to evaluate the association between different HRT types/methods use and risk of EC, and reveal this risk within different body mass index (BMI) groups. In whole cohort, 677 EC occurred during mean 11.6 years follow-up. Cox proportional hazards regression was used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs) with HRT status (never, former, or current) for risk of EC incidence. Current HRT use was not significantly associated with EC risk (HR for current vs. never HRT use: 1.13; 95% CI: 0.92, 1.38) in the whole cohort, but presented a dose-response effect on increased EC risk (HR for >10-year use vs. never HRT use: 1.73; 95% CI: 1.35, 2.21). Moreover, EC risk differed in distinct regimens or subsets (all Pinteraction < 0.05). Estrogen-only use was associated with elevated EC risk (HR for current vs. never HRT use: 1.51; 95% CI: 1.12, 2.04), but women with high BMI (> 30 kg/m2) who currently use estrogen-only harbored decreased EC risk (HR: 0.56; 95% CI: 0.38, 0.82) compared to counterparts without HRT use. Estrogen-only use is associated with increased EC risk, and precise monitoring of EC development for postmenopausal women with long-term HRT use are urgently needed. BMI could serve as an important surrogate to assess this risk.

Clinical issues of surgery for uterine endometrial cancer in Japan

Objective The mainstay of treatment for uterine endometrial cancer is surgery, and recurrent-risk cases require multidisciplinary treatment, including surgery, chemotherapy and radiation therapy. Methods The standard surgery for uterine endometrial cancer is hysterectomy and bilateral salpingooophorectomy, with additional retroperitoneal lymph node dissection and omentectomy, depending on the case. The appropriate treatment is determined based on the risk classification, such as the depth of invasion into the myometrium, diagnosis of histological type and grade, and risk assessment of lymph node metastasis. Results Recently, minimally invasive surgery has been widely used not only in low-risk patients but also in intermediate- and high-risk patients. In low-risk patients, the possibility of ovarian preservation is discussed from a healthcare perspective for young women. Determining the need for retroperitoneal lymph node dissection based on sentinel lymph node evaluation may contribute in minimizing the incidence of post-operative lymphedema while ensuring accurate diagnosis of lymph node metastasis. Recently, many studies using sentinel lymph nodes have been reported for patients with uterine endometrial cancer, and the feasibility of sentinel lymph node mapping surgery has been proven. Unfortunately, sentinel lymph node biopsy and sentinel lymph node mapping surgery have not been widely adopted in surgery for uterine cancer in Japan. In addition, the search for biomarkers, such as RNA sequencing using The Cancer Genome Atlas, metabolic profile and lipidomic profile for early detection and prognostic evaluation, has been actively pursued. Conclusions Gynecologic oncologists expect to be able to provide uterine endometrial cancer patients with appropriate treatment that preserves their quality of life without compromising oncologic outcomes in the near future.

Comprehensive Analysis of Copy Number Variation, Nucleotide Mutation, and Transcription Level of PPAR Pathway-Related Genes in Endometrial Cancer

Endometrial cancer is a common malignant tumor in gynecology, and the prognosis of advanced patients is dismal. Recently, many studies on the peroxisome proliferator-activated receptor pathway have elucidated its crucial involvement in endometrial cancer. Copy number variation (CNA) and nucleotide mutations often occur in tumor tissues, leading to abnormal protein expression and changes in protein structure. We analyzed the exon sequencing data of endometrial cancer patients in the TCGA database and found that somatic changes in PPAR pathway-related genes (PPAR-related-gene) often occur in UCEC patients. Patients with CNA or mutation changes in the exon region of the PPAR-related-gene usually have different prognostic outcomes. Furthermore, we found that the mRNA transcription and protein translation levels of PPAR-related-gene in UCEC are significantly different from that of adjacent tissues/normal uterus. The transcription level of some PPAR-related-gene (DBI, CPT1A, CYP27A1, and ME1) is significantly linked to the prognosis of UCEC patients. We further constructed a prognostic predicting tool called PPAR Risk score, a prognostic prediction tool that is a strong independent risk factor for the overall survival rate of UCEC patients. Comparing to the typical TNM classification system, this tool has higher prediction accuracy. We created a nomogram by combining PPAR Risk score with clinical characteristics of patients in order to increase prediction accuracy and promote clinical use. In summary, our study demonstrated that PPAR-related-gene in UCEC had significant alterations in CNA, nucleotide mutations, and mRNA transcription levels. These findings can provide a fresh perspective for postoperative survival prediction and individualized therapy of UCEC patients.

Staging of Endometrial Cancer Using Fusion T2-Weighted Images with Diffusion-Weighted Images: A Way to Avoid Gadolinium?

Endometrial cancer is the eighth most common cancer worldwide, and its prognosis depends on various factors, with myometrial invasion having a major impact on prognosis. Optimizing MRI protocols is essential, and it would be useful to improve the diagnostic accuracy without the need for other sequences. We conducted a retrospective, single-center study, which included a total of 87 patients with surgically confirmed primary endometrial cancer, and who had undergone a pre-operative pelvic MRI. All exams were read by an experienced radiologist dedicated to urogenital radiology, and the depth of myometrial invasion was evaluated using T2-Weighted Images (T2WI) and fused T2WI with Diffusion-Weighted Images (DWI). Both results were compared to histopathological evaluations. When comparing both sets of imaging (T2WI and fused T2WI-DWI images) in diagnosing myometrial invasion, the fused images had better accuracy, and this difference was statistically significant (p < 0.001). T2WI analysis correctly diagnosed 82.1% (70.6–88.7) of cases, compared to 92.1% correctly diagnosed cases with fused images (79.5–97.2). The addition of fused images to a standard MRI protocol improves the diagnostic accuracy of myometrial invasion depth, encouraging its use, since it does not require more acquisition time.

Chromatin topology defines estradiol-primed progesterone receptor and PAX2 binding in endometrial cancer cells

Estrogen (E2) and Progesterone (Pg), via their specific receptors (ERalpha and PR), are major determinants in the development and progression of endometrial carcinomas, However, their precise mechanism of action and the role of other transcription factors involved are not entirely clear. Using Ishikawa endometrial cancer cells, we report that E2 treatment exposes a set of progestin-dependent PR binding sites which include both E2 and progestin target genes. ChIP-seq results from hormone-treated cells revealed a non-random distribution of PAX2 binding in the vicinity of these estrogen-promoted PR sites. Altered expression of hormone regulated genes in PAX2 knockdown cells suggests a role for PAX2 in fine-tuning ERalpha and PR interplay in transcriptional regulation. Analysis of long-range interactions by Hi-C coupled with ATAC-seq data showed that these regions, that we call 'progestin control regions' (PgCRs), exhibited an open chromatin state even before hormone exposure and were non-randomly associated with regulated genes. Nearly 20% of genes potentially influenced by PgCRs were found to be altered during progression of endometrial cancer. Our findings suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with PAX2 to accessible chromatin regions. What maintains these regions open remains to be studied.

Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis

Background Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiology. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for cancer prevention.

Synthesis, spectral characterization and biological activities of Ag(I), Pt(IV) and Au(III) complexes with novel azo dye ligand (N,N,O) derived from 2-amino-6-methoxy benzothiazole

The novel ligand 2-[2'-(6-methoxybenzothiazolyl)azo]-3,5-dimethyl benzoic acid (6-MBTAMB), derived from 2-amino-6-methoxy benzothiazole, has been used to synthesize a series of new metal complexes of Ag(I), Pt(IV) and Au(III). The metal complexes were characterized by elemental analyses (CHNS), molar conductivity, crystal structure (XRD), spectroscopic techniques: FT-IR, 1H NMR, 13C NMR, UV-Vis, mass spectra, thermal analysis (TG-DTA), FE-SEM and magnetic properties. Results confirmed that the azo dye ligand behaves a tridentate and coordinates to the metal ion via nitrogen atom of azomethine group of heterocyclic benzothiazole ring, nitrogen atom of the azo group which is the farthest of the benzothiazole molecule and carboxylic oxygen. Antimicrobial properties of all newly synthesized azo compounds are also demonstrated against bacterial pathogenic organisms and fungi. These complexes are more effective against bacteria and less effective against fungi compared to standard antibacterial drugs (Novobiocin) and antifungal drugs (Cycloheximide). By using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging test, it was discovered that the complexes had good antioxidant properties. In addition, the (6-MBTAMB) and metal complexes were docked with the crystal structure of FGF Receptor 2 (FGFR2) kinase domain harboring the pathogenic gain of function K659E mutation identified in endometrial cancer using the Molecular Operating Environment module (MOE). In vitro studies on human endometrial cancer cell lines (MFE-296) as well as healthy human umbilical vein endothelial cells (HUVEC) show uptake of the intact compounds by the cancer cells and increased activity against the cancer cells.