When synchronous mucinous metaplasia and neoplasia of the female genital tract and peutz-jeghers syndrome meet: a case report and literature reviews.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is characterized by the presence of hamartomatous polyps in the gastrointestinal tract and mucocutaneous pigmentation on the lips, oral mucosa, nose, fingers, and toes. Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) refers to the occurrence of multifocal mucinous lesions in at least two sites, including the cervix, uterus, fallopian tubes, and ovaries, in the female genital tract. SMMN-FGT and PJS are rare diseases with a very low incidence, especially when occurring simultaneously. CASE PRESENTATION: We report a case in which a woman with a large mass on the left ovary underwent a gynecological surgery and was diagnosed with cervical gastric-type adenocarcinoma and mucinous lesions in the endometrium, bilateral fallopian tubes, and ovary, i.e., SMMN-FGT, by postoperative paraffin pathology. The patient sought medical attention for abdominal distension and enlargement. A gynecological ultrasound revealed a multilocular cystic mass in the pelvis, while serum tumor markers were within normal limits, with mildly elevated carbohydrate antigen 199 and carbohydrate antigen 125 levels. Cervical thin-prep cytology test result was negative. The patient had a family history of PJS with black spots on her skin and mucous membranes since the age of 8 years. She underwent multiple partial small bowel resections and gastrointestinal polypectomy owing to intestinal obstruction and intussusception. She underwent left adnexectomy, hysterectomy, right salpingectomy, greater omental resection, appendectomy and right ovary biopsy, and received six courses of adjuvant chemotherapy with Lopressor plus Carboplatin. Genetic testing revealed a heterozygous serine threonine kinase 11 germline mutation and there were no signs of recurrence during the 18-month follow-up period after treatment. CONCLUSIONS: This is a rare case in which PJS was complicated by SMMN-FGT. Owing to its extreme rarity, there are no guidelines, but reported cases appear to indicate a poor prognosis. We retrospectively reviewed all cases of collisions between PJS and SMMN-FGT and explored the clinical features, pathological characteristics, diagnosis, treatment methods, and prognosis when the two diseases coexisted. The aim is to deepen the clinicians' understanding of this disease for early detection, diagnosis and treatment.

SIRT1 as a potential therapeutic target in pelvic organ prolapse due to protective effects against oxidative stress and cellular senescence in human uterosacral ligament fibroblasts.

INTRODUCTION: The pathogenesis of pelvic organ prolapse (POP), an age-related disease, has not been fully elucidated. Therapeutic targets of POP are limited. Silencing information regulator 2 related enzyme 1 (SIRT1), a gene considered capable of regulating oxidative stress and cellular senescence, has been widely demonstrated involved in aging and age-related diseases. The present study aimed to explore the role of SIRT1 in POP in vivo and in vitro. METHODS: Expression levels of SIRT1 in uterosacral ligament (USL) tissues from patients with or without POP were measured using immunohistochemical assays. SRT1720, a SIRT1 agonist, was used to upregulate SIRT1, and hydrogen peroxide (H2O2) was used to establish an oxidative stress model in human uterosacral ligament fibroblasts (hUSLFs). The effects of SIRT1 on cell viability, apoptosis, senescence, and reactive oxygen species (ROS) levels were detected, respectively. Western blot assays were used to examine expression levels of apoptosis- and senescence-associated biomarkers. Unpaired Student's t test, Mann-Whitney U test, χ2 test, and one-way ANOVA were performed for determining statistically significant differences. RESULTS: Compared to the control group, expression levels of SIRT1 were downregulated in USL tissues and hUSLFs from patients with POP, and associated with stage (p < 0.05). hUSLFs of patients with POP had lower growth rates (p < 0.0001) than those of the control group, which were improved by upregulating SIRT1 (p < 0.05). The senescent proportion was higher in the POP group than the control group (43.63 ± 10.62% vs. 4.84 ± 5.32%, p < 0.0001), which could be reduced by upregulating SIRT1 (p < 0.0001). High ROS levels in the POP group were also alleviated by SRT1720. H2O2 exposure increased ROS levels, inhibited proliferation, and triggered apoptosis and senescence in hUSLFs of patients without POP in a concentration-dependent manner. Further, these damages were alleviated by pretreatment with SRT1720. CONCLUSIONS: SIRT1 is downregulated in patients with POP, and the development of SIRT1 activators or agonists may have applications in the treatment and prevention of POP through antioxidative stress and antisenescence effects.

Development of Nomogram Models Based on Peripheral Blood Score and Clinicopathological Parameters to Predict Preoperative Advanced Stage and Prognosis for Epithelial Ovarian Cancer Patients.

Purpose: Nutritional and inflammatory states are crucial in cancer development. The purpose of this study is to construct a scoring system grounded on peripheral blood parameters associated with nutrition and inflammation and explore its value in stage, overall survival (OS), and progression-free survival (PFS) prediction for epithelial ovarian cancer (EOC) patients. Patients and Methods: Four hundred and fifty-three EOC patients were retrospectively identified and their clinical data and relevant peripheral blood parameters were collected. The ratio of neutrophil to lymphocyte, lymphocyte to monocyte, fibrinogen to lymphocyte, total cholesterol to lymphocyte and albumin level were calculated and dichotomized. A scoring system named peripheral blood score (PBS) was constructed. Univariate and multivariate Logistic or Cox regression analyses were used to select independent factors; these factors were then used to develop nomogram models of advanced stage and OS, PFS, respectively. The internal validation and DCA analysis were performed to evaluate models. Results: Lower PBS indicated a better prognosis and higher PBS indicated inferior. High PBS is associated with advanced stage, high CA125, serous histological type, poor differentiation, and accompanied ascites. The logistic regression showed age, CA125, and PBS were independent factors for the FIGO III-IV stage. The nomogram models for advanced FIGO stage based on these factors showed good efficiency. FIGO stage, residual disease, and PBS were independent factors affecting OS and PFS, the nomogram models composed of these factors had good performance. DCA curves revealed the models augmented net benefits. Conclusion: PBS can be a noninvasive biomarker for EOC patients' prognosis. The related nomogram models could be powerful, cost-effective tools to provide information of advanced stage, OS, and PFS for EOC patients.

Tregs are involved in VEGFA/ VASH1-related angiogenesis pathway in ovarian cancer.

Vasohibin1 (VASH1) is a kind of vasopressor, produced by negative feedback from vascular endothelial growth factor A (VEGFA). Anti-angiogenic therapy targeting VEGFA is currently the first-line treatment for advanced ovarian cancer (OC), but there are still many adverse effects. Regulatory T cells (Tregs) are the main lymphocytes mediating immune escape function in the tumor microenvironment (TME) and have been reported to influence the function of VEGFA. However, whether Tregs are associated with VASH1 and angiogenesis in TME in OC is unclear. We aimed to explore the relationship between angiogenesis and immunosuppression in the TME of OC. We validated the relationship between VEGFA, VASH1, and angiogenesis in ovarian cancer and their prognostic implications. The infiltration level of Tregs and its marker forkhead box protein 3 (FOXP3) were explored in relation to angiogenesis-related molecules. The results showed that VEGFA and VASH1 were associated with clinicopathological stage, microvessel density and poor prognosis of ovarian cancer. Both VEGFA and VASH1 expression were associated with angiogenic pathways and there was a positive correlation between VEGFA and VASH1 expression. Tregs correlated with angiogenesis-related molecules and indicated that high FOXP3 expression is harmful to the prognosis. Gene set enrichment analysis (GSEA) predicted that angiogenesis, IL6/JAK/STAT3 signaling, PI3K/AKT/mTOR signaling, TGF-ß signaling, and TNF-α signaling via NF-κB may be common pathways for VEGFA, VASH1, and Tregs to be involved in the development of OC. These findings suggest that Tregs may be involved in the regulation of tumor angiogenesis through VEGFA and VASH1, providing new ideas for synergistic anti-angiogenic therapy and immunotherapy in OC.

Expression profile analysis of lncRNA and mRNA in uterosacral ligaments of women with pelvic organ prolapse by RNA-seq.

Pelvic organ prolapse (POP) is a conventional gynecological condition and the mechanism is not entirely clear. Although an increasing number of studies revealed that long non-coding RNAs (lncRNAs) have essential functions in many diseases, little knowledge has been acquired in POP. The current study aimed to investigate the regulatory mechanism of lncRNA in POP. In this report, we investigated the expression profile of lncRNAs and mRNAs between POP and the control groups in human uterosacral ligament (hUSL) tissues through RNA-seq. Cytoscape was used to construct a POP-specific lncRNA-mRNA network and select key molecules. This RNA-Seq analysis uncovered a total of 289 lncRNAs, and 41 lncRNAs and 808 mRNAs were differentially expressed between the POP and non-POP groups. Four lncRNAs were identified and validated by real-time PCR. The result of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) indicated that differentially expressed lncRNAs were abundant in the biological processes and signaling pathways concerned in POP. The differentially expressed lncRNAs were mainly enriched in protein binding, the single-organism cellular process, and cytoplasmic part. The network was constructed based on the correlation analyses of the abnormally expressed lncRNAs and their target proteins to imitate their interactions. Taken together, this study was the first to demonstrate the differential expression profiles of lncRNA in POP and normal tissues by sequencing technology. Our study indicated that lncRNAs could correlate with the development of POP and may be as significant genes in the diagnosis and treatment of POP.

Effectiveness of Self-cut vs Mesh-Kit Titanium-Coated Polypropylene Mesh for Transvaginal Treatment of Severe Pelvic Organ Prolapse: A Multicenter Randomized Noninferiority Clinical Trial.

Importance: Transvaginal mesh (TVM) can increase the durability of vaginal surgical procedures for pelvic organ prolapse (POP) and may be indicated in certain situations despite concerns about mesh-related complications. In addition, the expense of commercial mesh kits has limited their use. The effectiveness, safety, and cost of a self-cut mesh procedure compared with a commercial mesh-kit procedure for the surgical treatment of women with POP is unclear. Objective: To assess the 1-year effectiveness and safety of self-cut titanium-coated polypropylene mesh compared with a precut commercial mesh kit for the transvaginal surgical treatment of women with severe symptomatic POP. Design, Setting, and Participants: This multicenter randomized noninferiority clinical trial was conducted at 11 hospitals in 8 provinces of China. A total of 336 women with symptomatic stage 3 to 4 POP were enrolled between January 22, 2018, and November 11, 2019, with follow-up through December 11, 2020. Interventions: Participants were randomized to receive a TVM procedure using either self-cut mesh (self-cut mesh group) or a precut commercial mesh kit (mesh-kit group), both of which used the same titanium-coated polypropylene mesh. Main Outcomes and Measures: The primary outcome measure was composite surgical success at 1 year, which was defined as the absence of vaginal bulge symptoms, no additional retreatment for POP, and no vaginal prolapse at or beyond the hymen. Secondary outcomes included symptom-specific pelvic floor function and quality-of-life measures as well as perioperative complications, including mesh-related complications and hospitalization costs. Complications were categorized using the Clavien-Dindo system (with grade 1 indicating any deviation from the normal postoperative course but not requiring grade 2-4 interventions; grade 2, need for pharmacological treatment, blood transfusion, and/or total parenteral nutrition; grade 3, the need for surgical, endoscopic, and/or interventional radiological procedures; and grade 4, life threatening). Results: Among 336 female participants (mean [SD] age, 63.3 [5.9] years; all of Chinese ethnicity), 169 patients were randomized to the self-cut mesh group, and 167 were randomized to the mesh-kit group. Three patients were unavailable for follow-up after 1 year. In the intention-to-treat analysis, 162 women (95.9%) in the self-cut mesh group had outcomes that met the definition of surgical success; this result was noninferior to the surgical success rate observed in the mesh-kit group (146 women [87.4%]; risk difference, 8.5%; 95% CI, 2.2%-14.3%; P = .006). The frequency of Clavien-Dindo grade 1 to 3 perioperative complications was not significant between groups (12 of 166 women [7.2%] in the self-cut mesh group vs 20 of 161 women [12.4%] in the mesh-kit group; P = .14). Vaginal mesh exposure rates in women examined at 1 year were similar (4 women [2.4%] in the self-cut mesh group vs 8 women [4.8%] in the mesh-kit group; P = .23). Median (IQR) total hospitalization costs were $3663.00 ($3258.90-$4495.10) in the self-cut mesh group vs $6144.00 ($5434.90-$7160.20) in the mesh-kit group (P < .01), representing savings of $2481.00 (40.4%) with the use of self-cut mesh. Conclusions and Relevance: In this clinical trial, the composite surgical success rate of a self-cut mesh procedure was noninferior to that of a commercial mesh-kit procedure using the same titanium-coated polypropylene mesh and reduced hospitalization expenses by 40.4%. These findings suggest that the use of self-cut mesh procedures may be advantageous for the surgical treatment of some women with severe POP, particularly those in countries with low and middle income. Trial Registration: ClinicalTrials.gov identifier: NCT03283124.

The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Efficacy of the bromodomain 4 (BRD4) inhibitor JQ1 has been reported for the treatment of various human cancers, but its potential impact on EC remains unclear. We therefore aimed to elucidate the function of BRD4 and the effects of JQ1 in EC in vivo and in vitro. METHODS: The mRNA expression of BRD4 was evaluated using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). BRD4 protein expression in EC tissues was measured using immunohistochemistry (IHC) assays. The effects of JQ1 on EC were determined by using MTT and colony formation assays, flow cytometry and xenograft mouse models. The underlying mechanism was also examined by western blot and small interfering RNA (siRNA) transfection. RESULTS: BRD4 was overexpressed in EC tissues, and the level of BRD4 expression was strongly related to poor prognosis. The BRD4-specific inhibitor JQ1 suppressed cell proliferation and colony formation and triggered cell apoptosis, cell cycle arrest, and changes in the expression of proteins in related signaling pathways. Moreover, JQ1 decreased the protein expression of BRD4 and c-Myc, and knockdown of BRD4 or c-Myc reduced the viability of EC cells. Intraperitoneal administration of JQ1 (50 mg/kg) significantly suppressed the tumorigenicity of EC cells in a xenograft mouse model. CONCLUSION: Our results demonstrate that BRD4 is a potential marker of EC and that the BRD4 inhibitor JQ1 is a promising chemotherapeutic agent for the treatment of EC.

Developing a validated nomogram for predicting ovarian metastasis in endometrial cancer patients: a retrospective research.

OBJECTIVE: To explore risk factors and develop a prediction model for ovarian metastasis in endometrial cancer (EC), as well as providing provide a reference for clinical ovarian preservation. METHODS: We conducted a retrospective observational study enrolling 1496 EC patients having received complete staging surgery from Qilu Hospital of Shandong University from 2012 to 2018. These patients were randomly divided into two cohorts: training cohort (n = 1046) and validation cohort (n = 448). A nomogram prediction model was developed based on univariate, least absolute shrinkage and selection operator (Lasso), and multivariate logistic regression. Then, the nomogram model's performance was evaluated in discrimination, calibration, and clinical utility three aspects. RESULTS: Parametrium invasion, lymph node metastasis, and oviduct metastasis were finally contained in the nomogram prediction model. The AUC of the model in the training cohort was 0.85 compared with 0.72 in the validation cohort. It also behaved well in calibration and had good clinical utility. With a threshold probability of 20% ~ 80%, the nomogram increased the net benefit by 0 ~ 13.6 per 100 patients than surgery for all patients upon validation. CONCLUSIONS: We develop a nomogram with good performances for predicting ovarian metastasis in EC patients, which may help clinicians identify candidate patients appropriate for ovarian preservation in premenopausal EC patients.

Low Density Lipoprotein Receptor (LDLR) and 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase (HMGCR) Expression are Associated with Platinum-Resistance and Prognosis in Ovarian Carcinoma Patients.

PURPOSE: The efficacy of post-surgery platinum-based chemotherapy, the primary choice for the treatment of ovarian cancer (OC), is greatly reduced by the development of drug-resistance. In this study, we investigated the association of expression low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), two cholesterol metabolism-related proteins, in OC tissues and chemoresistance and patient prognosis. METHODS: Survival analysis using LDLR and HMGCR expression in the ovarian cancer patients using the dataset of Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was carried out online. A retrospective study was performed on 65 patients who had undergone surgery for ovarian cancer. In addition, patients were divided into 2 groups: platinum resistance group and platinum sensitivity group. Serum lipid metabolism data were collected and analyzed. Protein expressions of LDLR and HMGCR in ovarian cancer tissue were detected by immunohistochemistry. RESULTS: Online survival analysis showed that patients with higher LDLR expression had poorer prognosis than those with lower LDLR expression in ovarian cancer cells, while a higher HMGCR expression was associated with better OC prognosis. Overall survival (OS) and disease-free survival (DFS) were lower in patients with higher LDLR levels (OS: P=0.046, DFS: P=0.009). Platinum-resistant patients had higher levels of low-density lipoprotein (LDL) and cholesterol in serum as compared with platinum-sensitive patients (P<0.001). Immunohistochemistry showed that LDLR expression was high and HMGCR was low in platinum-resistant patients. CONCLUSION: The expression of LDLR and HMGCR proteins, involved in the regulation of cholesterol metabolism and the plasma LDL and cholesterol levels were significantly different in platinum-resistant and platinum-sensitive ovarian cancer patients. We postulate that cholesterol metabolic reprogramming might play a role in platinum resistance in ovarian cancer.

Identification of Three Potential Prognostic Genes in Platinum-Resistant Ovarian Cancer via Integrated Bioinformatics Analysis.

PURPOSE: Ovarian cancer is the most lethal gynecologic malignancy. Resistance to platinum-based chemotherapy affects the overall survival of patients. This study used an integrated bioinformatics to find the poorly understood molecular mechanisms underlying platinum resistance in ovarian cancer. METHODS: Based on the RNA-seq data of tissues in The Cancer Genome Atlas (TCGA) and RNA-seq data of cells from the Cancer Cell Encyclopedia (CCLE), we integrated differentially expressed genes (DEGs) in ovarian cancer tissue and cells. After screening for DEGs related to platinum resistance, we conducted survival analysis and built protein interaction networks to identify genes that may affect prognosis and interact with each other. Least absolute shrinkage and selection operator (Lasso) regression analysis was used to construct a predictive model. Immunohistochemistry and Western blot were used to validate the results. Finally, gene set enrichment analysis (GSEA) was performed on the expression of genes individually. RESULTS: We found that ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) interacted with each other and could predict resistance to platinum-based therapy, correlating negatively with prognosis. Moreover, we constructed a predictive model based on nine genes, including ATP1A2 and CASQ2. Immunohistochemistry and Western blot validated the upregulation of these genes in ovarian cancer tissue samples and cell lines. The immunohistochemistry results also confirmed the prognostic value of ATP1A2, CASQ2 and RYR2. GSEA predicted that ATP1A2, CASQ2 and RYR2 may act on the KRAS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells. CONCLUSION: ATP1A2, CASQ2 and RYR2 were highly expressed in platinum-resistant ovarian cancer. ATP1A2 and CASQ2 were related to the prognosis of platinum-resistant ovarian cancer patients. These genes might act on KARS and mTORC1 pathways and participate in metabolic reprogramming and regulation of calcium homeostasis in platinum-resistant cells.

Corrigendum: Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K-AKT Pathway and Activating the AMPK-ROS Pathway.

[This corrects the article DOI: 10.3389/fonc.2021.642229.].

GABPA Expression in Endometrial Carcinoma: A Prognostic Marker.

BACKGROUND: GA-binding protein A (GABPA), a transcription factor, is broadly involved in physiological and pathological processes. Several studies have investigated the relationship between GABPA expression level and outcomes of various malignancies. However, the function and clinicopathological significance of GABPA in endometrial carcinoma (EC) remain obscure. METHODS: The GABPA mRNA expression in EC tissues and adjacent nonneoplastic tissues in the TCGA database was involved in our study. The protein expression of GABPA in 107 EC tissues and 15 normal endometrial tissues was detected by immunohistochemistry. RESULTS: The GABPA expression was significantly downregulated in EC tissues compared with its expression in normal tissues (P < 0.001). The expression of GABPA was markedly correlated with type II EC (P < 0.01) and grade 3 EC (P < 0.05). A tendency has been observed that patients with low GABPA levels had relatively poorer overall survival (OS) (P = 0.036) and disease-free survival (DFS) (P = 0.016) than patients with high GABPA levels. The multivariate Cox proportional hazard model showed that lower expression of GABPA was an independent poor prognostic factor for OS (P = 0.043) and DFS (P = 0.045). Similar correlation between low expression levels of GABPA and unfavorable prognosis has also been found in type II or grade 3 EC. IHC analysis showed EC tissues had low expression of GABPA, which indicated relatively poor prognosis. Moreover, we identified that the GABPA mRNA expression was negatively correlated with its methylation level (R = -0.2512, P < 0.001) which is one of the mechanisms for the silencing of GABPA gene. CONCLUSION: GABPA may act as an independent predictor of clinical prognosis and serve as a potential target gene for EC therapy.

Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K-AKT Pathway and Activating the AMPK-ROS Pathway.

Background: Ovarian cancer is the most lethal female genital malignancy. Although cisplatin is the first-line chemotherapy to treat ovarian cancer patients along with debulking surgeries, its efficacy is limited due to the high incidence of cisplatin resistance. ATP citrate lyase (ACLY) has been shown to be a key metabolic enzyme and is associated with poor prognosis in various cancers, including ovarian cancer. Nevertheless, no studies have probed the mechanistic relationship between ACLY and cisplatin resistance. Methods: Survival analysis was mainly carried out online. Bioinformatic analysis was performed in R/R studio. Proliferative activity was measured by MTT and colony formation assays. Cell cycle and apoptosis analysis were performed by flow cytometry. The acquired-cisplatin-resistant cell line A2780/CDDP was generated by exposing A2780 to cisplatin at gradually elevated concentrations. MTT assay was used to calculate IC50 values of cisplatin. A xenograft tumor assay was used test cell proliferation in vivo. Results: Higher expression of ACLY was found in ovarian cancer tissue and related to poor prognosis. Knockdown of ACLY in A2780, SKOV3, and HEY cells inhibited cell proliferation, caused cell-cycle arrest by modulating the P16-CDK4-CCND1 pathway, and induced apoptosis probably by inhibiting p-AKT activity. Bioinformatic analysis of the GSE15709 dataset revealed upregulation of ACLY and activation of PI3K-AKT pathway in cells with acquired cisplatin resistance, in line with observations on A2780/CDDP cells that we generated. Knockdown of ACLY alleviated cisplatin resistance, and works synergistically with cisplatin treatment to induce apoptosis in A2780/CDDP cells by inhibiting the PI3K-AKT pathway and activating AMPK-ROS pathway. The ACLY-specific inhibitor SB-204990 showed the same effect. In A2780/CDDP cells, AKT overexpression could attenuate cisplatin re-sensitization caused by ACLY knockdown. Conclusions: Knockdown of ACLY attenuated cisplatin resistance by inhibiting the PI3K-AKT pathway and activating the AMPK-ROS pathway. These findings suggest that a combination of ACLY inhibition and cisplatin might be an effective strategy for overcoming cisplatin resistance in ovarian cancer.

Overexpression of Nucleolin is a Potential Prognostic Marker in Endometrial Carcinoma.

PURPOSE: Nucleolin (NCL) is a multifunctional protein with oncogenic properties. NCL expression levels have been linked to the outcomes of various malignancies, but the clinical value of NCL in patients with endometrial carcinoma (EC) remains unclear. Here, the expression of NCL in EC tissues and its associations with patient outcomes were assessed. PATIENTS AND METHODS: Data on NCL mRNA expression in EC and adjacent nonneoplastic tissues from The Cancer Genome Atlas (TCGA) were analyzed. In addition, NCL protein expression in 82 endometroid endometrial adenocarcinoma tissues and 15 non-malignant tissues was detected by immunohistochemistry. RESULTS: Elevated NCL expression was markedly correlated with serous endometrial carcinoma (P<0.001), advanced stage (P=0.029), and grade 3 (P<0.001). High NCL levels were associated with poorer overall survival (OS) and disease-free survival (DFS) compared with intermediate or low NCL levels (OS: P=0.001, DFS: P=0.006). The multivariate Cox proportional hazards model showed that NCL expression was an independent poor prognostic factor for DFS (HR=1.282, CI=1.027-1.601, P=0.028). A similar correlation between high expression levels of NCL and unfavorable DFS was found in endometrioid endometrial adenocarcinoma (HR=1.411, CI=1.083-1.840, P=0.011). Positive extra-nuclear NCL expression (HR=3.377, 95% CI=1.029-11.186, P=0.046) and low nuclear NCL expression (HR=0.233, 95% CI=0.068-0.796, P=0.020) were independent prognostic factors for DFS in endometrioid endometrial adenocarcinoma. CONCLUSION: Heterotopic NCL is a potential prognostic biomarker for EC. Inhibiting the distribution of NCL from the nucleus to the cytoplasm and membrane may be a promising therapeutic strategy to improve outcomes in patients with EC with high NCL expression.

A 14-year multi-institutional collaborative study of Chinese pelvic floor surgical procedures related to pelvic organ prolapse.

BACKGROUND: It has been a global trend that increasing complications related to pelvic floor surgeries have been reported over time. The current study aimed to outline the development of Chinese pelvic floor surgeries related to pelvic organ prolapse (POP) over the past 14 years and investigate the potential influence of enhanced monitoring conducted by the Chinese Association of Urogynecology since 2011. METHODS: A total of 44,594 women with POP who underwent pelvic floor surgeries between October 1, 2004 and September 30, 2018 were included from 22 tertiary academic medical centers. The data were reported voluntarily and obtained from a database. We compared the proportion of each procedure in the 7 years before and 7 years after September 30, 2011. The data were analyzed by performing Z test (one-sided). RESULTS: The number of different procedures during October 1, 2011-September 30, 2018 was more than twice that during October 1, 2004-September 30, 2011. Regarding pelvic floor surgeries related to POP, the rate of synthetic mesh procedures increased from 38.1% (5298/13,906) during October 1, 2004-September 30, 2011 to 46.0% (14,107/30,688) during October 1, 2011-September 30, 2018, whereas the rate of non-mesh procedures decreased from 61.9% (8608/13,906) to 54.0% (16,581/30,688) (Z = 15.53, P < 0.001). Regarding synthetic mesh surgeries related to POP, the rates of transvaginal placement of surgical mesh (TVM) procedures decreased from 94.1% (4983/5298) to 82.2% (11,603/14,107) (Z = 20.79, P < 0.001), but the rate of laparoscopic sacrocolpopexy (LSC) procedures increased from 5.9% (315/5298) to 17.8% (2504/14,107). CONCLUSIONS: The rate of synthetic mesh procedures increased while that of non-mesh procedures decreased significantly. The rate of TVM procedures decreased while the rate of LSC procedures increased significantly. TRIAL REGISTRATION NUMBER: NCT03620565, https://register.clinicaltrials.gov.

Association between BRCA mutations and endometrial carcinoma: a systematic review with meta-analysis.

PURPOSE: To first investigate on the association between BRCA mutations and endometrial carcinoma. To first evaluate the contribution of tamoxifen use and risk-reducing bilateral salping-oophenrectomy (BSO) on endometrial carcinoma in BRCA carriers. METHODS: A systematic search of electronic databases including the PubMed and EMBASE was conducted to identify publications exploring the association between BRCA mutations and endometrial carcinoma. Finally, single rate meta-analysis and diagnostic meta-analysis were performed. RESULTS: 11 retrospective studies and 3 prospective studies were included in the meta-analysis, single rate meta-analysis was performed on retrospective studies and prospective studies respectively. We got that incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Diagnostic meta-analysis performed on prospective studies found that tamoxifen increased incidence of endometrial carcinoma in BRCA carriers. CONCLUSIONS: The incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035 according to present studies, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Tamoxifen use is a certain risk factor for subsequent endometrial carcinoma, while history of breast cancer or risk-reducing BSO is not associated with incidence of follow-up endometrial carcinoma. The necessity and rationality of prophylactic hysterectomy for BRCA carriers remained to be discussed.

Oncogenic Role of NUPR1 in Ovarian Cancer.

BACKGROUND: Nuclear protein 1 (NUPR1) plays a critical role in the development and progression of various types of human cancers. However, the role and mechanism of NUPR1 in ovarian cancer have not been elucidated. The purpose of this study was to investigate the effect of NUPR1 on ovarian cancer in vivo and in vitro. MATERIALS AND METHODS: Through the pretreatment of ovarian cancer cell lines, including A2780 and SKOV3 cells, the expression of NUPR1 was detected by RT-PCR and Western blot assays. When NUPR1 was overexpressed and knocked down in A2780 cells and overexpressed in SKOV3 cells, the MTT assays, colony formation assays and EdU assays were used to detect cell proliferation. Furthermore, cell invasion and migration ability were detected with the transwell assays. Cell cycle and apoptosis of A2780 cells after small interfering RNA-NUPR1 (siRNA-NUPR1) were detected by flow cytometry assays. Finally, the effect of NUPR1 gene silencing on the growth of ovarian cancer was evaluated by tumor xenograft experiment in vivo. RESULTS: The expression of NUPR1 protein in A2780 cells was significantly higher than that in ovarian surface epithelium (OSE) cells (P < 0.05). The results showed that downregulation of NUPR1 gene expression significantly inhibited the proliferation, migration and invasion ability of A2780 cells, and increased apoptosis of A2780 cells, which expressed relatively high levels of NUPR1. And the expression of apoptosis-related proteins caspase 3, caspase 9 and Bax was upregulated when NUPR1 was knocked out, while the expression of anti-apoptotic proteins of Bcl-2 and Bcl-xl was downregulated. At the same time, the opposite results were observed when NUPR1 was overexpressed in A2780 and SKOV3 cells. Notably, the effect of NUPR1 overexpression in A2780 cells could be partially or completely eliminated by treatment with the AKT inhibitor LY294002. In addition, NUPR1 knockdown could effectively inhibit tumor growth of mice in vivo. CONCLUSION: In summary, NUPR1 has a carcinogenic effect in ovarian cancer, and the oncogenic effect of NUPR1 in ovarian cancer may be achieved by the AKT pathway.

Long non-coding RNA PTPRG-AS1 promotes cell tumorigenicity in epithelial ovarian cancer by decoying microRNA-545-3p and consequently enhancing HDAC4 expression.

BACKGROUND: Long non-coding RNA PTPRG antisense RNA 1 (PTPRG-AS1) deregulation has been reported in various human malignancies and identified as an important modulator of cancer development. Few reports have focused on the detailed role of PTPRG-AS1 in epithelial ovarian cancer (EOC) and its underlying mechanism. This study aimed to determine the physiological function of PTPRG-AS1 in EOC. A series of experiments were also performed to identify the mechanisms through which PTPRG-AS1 exerts its function in EOC. METHODS: Reverse transcription-quantitative polymerase chain reaction was used to determine PTPRG-AS1 expression in EOC tissues and cell lines. PTPRG-AS1 was silenced in EOC cells and studied with respect to cell proliferation, apoptosis, migration, and invasion in vitro and tumor growth in vivo. The putative miRNAs that target PTPRG-AS1 were predicted using bioinformatics analysis and further confirmed in luciferase reporter and RNA immunoprecipitation assays. RESULTS: Our data verified the upregulation of PTPRG-AS1 in EOC tissues and cell lines. High PTPRG-AS1 expression was associated with shorter overall survival in patients with EOC. Functionally, EOC cell proliferation, migration, invasion in vitro, and tumor growth in vivo were suppressed by PTPRG-AS1 silencing. In contrast, cell apoptosis was promoted by loss of PTPRG-AS1. Regarding the mechanism, PTPRG-AS1 could serve as a competing endogenous RNA in EOC cells by decoying microRNA-545-3p (miR-545-3p), thereby elevating histone deacetylase 4 (HDAC4) expression. Furthermore, rescue experiments revealed that PTPRG-AS1 knockdown-mediated effects on EOC cells were, in part, counteracted by the inhibition of miR-545-3p or restoration of HDAC4. CONCLUSIONS: PTPRG-AS1 functioned as an oncogenic lncRNA that aggravated the malignancy of EOC through the miR-545-3p/HDAC4 ceRNA network. Thus, targeting the PTPRG-AS1/miR-545-3p/HDAC4 pathway may be a novel strategy for EOC anticancer therapy.