Construction of a ceRNA network of hub genes affecting immune infiltration in ovarian cancer identified by WGCNA.

BACKGROUND: Ovarian cancer is the leading cause of death among gynecological malignancies. Immunotherapy has demonstrated potential effects in ovarian cancer. However, few studies on immune-related prognostic signatures in ovarian cancer have been reported. This study aimed to identify hub genes associated with immune infiltrates to provide insight into the immune regulatory mechanisms in ovarian cancer. METHODS: Raw data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) and University of California, Santa Cruz (UCSC) Xena websites. Single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were used to identify hub genes. Kaplan-Meier analysis and differential expression analysis were applied to explore the real hub genes. RESULTS: Through ssGSEA and WGCNA, 7 hub genes (LY9, CD5, CXCL9, IL2RG, SLAMF1, SLAMF6, and SLAMF7) were identified. Finally, LY9 and SLAMF1 were recognized as the real hub genes in immune infiltrates of ovarian cancer. LY9 and SLAMF1 are classified as SLAM family receptors involved in the activation of hematopoietic cells and the pathogenesis of multiple malignancies. Furthermore, 12 lncRNAs and 43 miRNAs significantly related to the 2 hub genes were applied to construct a lncRNA-miRNA-mRNA ceRNA network. The lncRNA-miRNA-mRNA ceRNA network shows upstream regulatory sites of the 2 hub genes. CONCLUSIONS: These findings improve our understanding of the regulatory mechanism of and reveal potential immune checkpoints for immunotherapy for ovarian cancer.

Tubal choriocarcinoma presented as ruptured ectopic pregnancy: a case report and review of the literature.

BACKGROUND: Tubal choriocarcinoma is an extremely rare but highly malignant trophoblastic tumor, which may be either gestational or non-gestational in origin. Due to atypical clinical manifestations and symptoms similar to ectopic pregnancy, it is easily to be confused with ectopic pregnancy. In addition, inadequate understanding of this rare disease by clinicians often leads to misdiagnosis or missed diagnosis, which in turn results in delayed treatment or even tumor metastasis. CASE PRESENTATION: This report summarized a case of a woman who was finally diagnosed as tubal choriocarcinoma through the follow-up of serum ß hCG levels and histopathological results after undergoing salpingectomy for being misdiagnosed as ectopic pregnancy. Five courses of adjuvant chemotherapy (5-fluorouracil, actinomycin-D, vinorelbine regime) have been administered to the patient in the prevention of any recurrences. During 1-year follow-up, the patient was asymptomatic and presented no evidence of recurrence. CONCLUSIONS: Tubal choriocarcinoma is easily to be confused with ectopic pregnancy. By analyzing this case and previous related cases, we aimed to provide references for clinicians in the diagnosis and treatment of tubal choriocarcinoma.

Successful pregnancy after complete resection of leiomyomatosis peritonealis disseminate without recurrence:a case report with next-generation sequencing analysis and literature review.

BACKGROUND: Peritoneal leiomyomatosis disseminate (LPD) is a rare disease characterized by widespread dissemination of leiomyomas nodules throughout the peritoneal and omental surfaces. Reports of pregnancy with LPD are even rarer. Therefore, there is no clear consensus on the treatment of LPD on pregnancy, and the pathogenesis is still unclear. CASE PRESENTATION: We reported a case of LPD patient who developed during pregnancy. The patient underwent a cesarean section at 32 weeks of gestation while removing all visible tumors, and no LPD lesions were seen in the subsequent cesarean section at full term. NGS of LPD lesions detected 4 mutations with focal high-level amplifications of CDK4 (cyclin-dependent kinases 4), NBN (Nibrin), DAXX (death domain associated protein), and MYC (myelocytomatosis oncogene). Immunohistochemistry staining analysis among benign leiomyoma, LPD, and leiomyosarcoma verified that LPD was an unusual intermediate between benign and malignant uterine smooth muscle tumors. Besides, LPD is a hormonal-dependent leiomyoma. After a detailed literature search, we summarized the detailed clinical features and follow-up information of patients with LPD during pregnancy. CONCLUSIONS: This is the first reported LPD case of successful term pregnancy without recurrence, following resection of all visible lesions in a prior pregnancy. LPD is an unusual intermediate between benign and malignant uterine smooth muscle tumors.

SUSD2 promotes cancer metastasis and confers cisplatin resistance in high grade serous ovarian cancer.

The activation of Notch3 is associated with potential progression of ovarian cancer, tumor invasion, metastasis and chemoresistance, which account for poor prognosis of high grade serous ovarian cancer (HGSOC). However, the underlying mechanisms of Notch3 are not yet very clear. Here we show that SUSD2 is one of Notch3-regulating genes and the elevated protein expression of SUSD2 in HGSOC. We also found that its high expression level was significantly correlated with worse overall survival, early recurrence and lymph nodes metastasis. Moreover, overexpression of SUSD2 in ovarian cancer cells promoted epithelial-mesenchymal transition (EMT) and the metastatic capacity of malignant cells. In contrast, silencing SUSD2 in aggressive ovarian cancer cells inhibited these processes both in vitro and in vivo. Mechanistically, we found SUSD2 promoted EMT through regulating the expression of EpCAM and EpCAM silencing reversed SUSD2-induced E-cadherin reduction and cells migration. Further experiments indicated a role of SUSD2 in conferring cisplatin resistance in ovarian cancer probably through enhancing autophagy in vitro. Collectively, these findings shed a new insight into the role of Notch3 downstream gene SUSD2 and provided a new therapeutic target for HGSOC.

Curcumin induces apoptotic cell death and protective autophagy by inhibiting AKT/mTOR/p70S6K pathway in human ovarian cancer cells.

PURPOSE: Curcumin (Cur), a yellow-colored dietary flavor from the plant (Curcuma longa), has been demonstrated to potentially resist diverse diseases, including ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with curcumin resistance in ovarian cancer still remains unclear. The aim of our study was to investigate the effects of curcumin on autophagy in ovarian cancer cells and elucidate the underlying mechanism. METHODS: In our study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), EdU proliferation assay and colony-forming assay were used to assess cell viability. Apoptosis was detected by western blot and flow cytometric analysis of apoptosis. Autophagy was defined by both electron microscopy and immunofluorescence staining markers such as microtubule-associated protein 1 light chain 3 (LC3). Plasmid construction and shRNA transfection helped us to confirm the function of curcumin. RESULTS: Curcumin reduced cell viability and induced apoptotic cell death by MTT assay in human ovarian cancer cell lines SK-OV-3 and A2780 significantly. Electron microscopy, western blot and immunofluorescence staining proved that curcumin could induce protective autophagy. Moreover, treatment with autophagy-specific inhibitors or stable knockdown of LC3B by shRNA could markedly enhance curcumin-induced apoptosis. Finally, the cells transiently transfected with AKT1 overexpression plasmid demonstrated that autophagy had a direct relationship with the AKT/mTOR/p70S6K pathway. CONCLUSIONS: Curcumin can induce protective autophagy of human ovarian cancer cells by inhibiting the AKT/mTOR/p70S6K pathway, indicating the synergistic effects of curcumin and autophagy inhibition as a possible strategy to overcome the limits of current therapies in the eradication of epithelial ovarian cancer.

PCNA-associated factor P15PAF , targeted by FOXM1, predicts poor prognosis in high-grade serous ovarian cancer patients.

Activation of the FOXM1 signaling pathway and the PI3K/AKT/mTOR signaling pathway is associated with poor prognosis in ovarian cancer. In this study, we demonstrated that P15PAF (KIAA0101) was significantly upregulated in high-grade serous ovarian cancer (HGSOC) and that high KIAA0101 expression was associated with poor prognosis. FOXM1 transcriptionally activated KIAA0101 to drive proliferation and metastasis of ovarian cancer cells. KIAA0101 activated the PI3K/AKT/mTOR signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in ovarian cancer cells resulting in cisplatin resistance. Thus, KIAA0101 was closely related to the FOXM1 and PI3K/AKT/mTOR signaling pathways. Collectively, these findings provide insights into the mechanisms of poor prognosis of ovarian cancer and have implications for the development of both predictive and therapeutic biomarkers for the treatment of ovarian cancer.

Spliceosome-associated factor CTNNBL1 promotes proliferation and invasion in ovarian cancer.

Ovarian cancer is the most lethal gynecologic malignancy and the molecular pathogenesis of high-grade serous ovarian carcinoma has not been completely characterized. Numerous studies have shown that altered splicing patterns and splicing factors were found to contribute to tumor development and progression. In this study, we demonstrated that spliceosome-associated factor CTNNBL1 was significantly upregulated in high-grade serous ovarian carcinoma, the elevated level of CTNNBL1 indicates poor prognosis in patients with high-grade serous ovarian carcinoma. Functional characterization revealed that CTNNBL1 promoted the proliferation and invasion of ovarian cancer cells in vitro. Furthermore, through transcriptome analysis, we found CTNNBL1 regulates multiple splicing events and gene expression in ovarian cancer cells. Importantly, we identified IFI16 and FOXM1 splicing was regulated by CTNNBL1. To our knowledge, this is the first study exploring the expression, functional roles and regulated splicing events of CTNNBL1 in ovarian cancer.

A 2-Protein Signature Predicting Clinical Outcome in High-Grade Serous Ovarian Cancer.

OBJECTIVE: High-grade serous ovarian cancer (HGSOC) accounts for approximately 70% deaths in ovarian cancer. The overall survival (OS) of HGSOC is poor and still remains a clinical challenge. High-grade serous ovarian cancer can be divided into 4 molecular subtypes. The prognosis of different molecular subtypes is still unclear. We aimed to investigate the prognostic values of immunohistochemistry-based different molecular subtypes in patients with HGSOC. METHODS: We analyzed the protein expression of representative biomarkers (CXCL11, HMGA2, and MUC16) of 3 different molecular subtypes in 110 formalin-fixed, paraffin-embedded HGSOC by tissue microarrays. RESULTS: High CXCL11 expression predicted worse OS, not disease-free survival (DFS; P = 0.028 for OS, P = 0.191 for DFS). High HMGA2 expression predicted worse OS and DFS (P = 0.037 for OS, P = 0.021 for DFS). MUC16 expression was not associated with OS or DFS (P = 0.919 for OS, P = 0.517 for DFS). Multivariate regression analysis showed that CXCL11 combined with HMGA2 signature was an independent predictor for OS and DFS in patients with HGSOC. CONCLUSIONS: CXCL11 combined with HMGA2 signature was a clinically applicable prognostic model that could precisely predict an HGSOC patient's OS and tumor recurrence. This model could serve as an important tool for risk assessment of HGSOC prognosis.

Efficacy of poly (ADP-ribose) polymerase inhibitors monotherapy and the impact to subsequent platinum-based chemotherapy in breast cancer susceptibility genes1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse.

BACKGROUND: The therapeutic effect of poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy compared with platinum-based chemotherapy, and the impact to subsequent platinum-based chemotherapy after PARPi resistance were inconclusive in breast cancer susceptibility genes (BRCA)1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse. METHODS: BRCA1/2-mutated patients with secondary platinum-sensitive relapse included in this study did not receive any maintenance regimen after first- and second-line platinum-based chemotherapy, and the secondary platinum-free interval (PFI) was more than 6 months. Patients in study group were treated with PARPi monotherapy until disease progression, and patients in control group were treated with platinum-based chemotherapy without restriction. Progression-free survival (PFS) was defined as the time from third-line therapy to disease progression or death, PFS2 was defined as the time from platinum-based chemotherapy after PARPi resistance to next subsequent therapy or death. Post-recurrence survival (PRS) refers to the survival time after secondary platinum-sensitive relapse. RESULTS: A total of 119 patients were retrospectively analyzed, including 71 (59.7%) in study group and 48 (40.3%) in control group. The objective response rate (ORR: 77.5% vs. 80.0%, p=0.766) and PFS (median: 11.2 vs. 11.0 months, p=0.962) were comparable. The benefit of subsequent platinum-based chemotherapy after PARPi resistance was more pronounced in patients with PARPi treatment for more than 12 months (median PFS2: 8.6 vs. 4.3 months, p=0.040). PARPi monotherapy had no adverse effect on PRS compared with platinum-based chemotherapy (median PRS:41.2 vs. 42.8 months, p=0.323). Compared to patients in control group who had never received PARPi, PARPi monotherapy (median PRS: 41.2 vs. 33.7 months, p=0.019) and post-line treatment with PARPi in the control group (median PRS: 48.1 vs. 33.7 months, p=0.002) could prolong PRS for patients with secondary platinum-sensitive relapse. CONCLUSIONS: PARPi monotherapy was similar to platinum-based chemotherapy for BRCA1/2-mutated ovarian cancer patients with secondary platinum-sensitive recurrence, and could improve prognosis.

Antiangiogenic Strategies in Epithelial Ovarian Cancer: Mechanism, Resistance, and Combination Therapy.

Angiogenesis is one of the hallmarks of cancer and plays a crucial role in carcinogenesis and progression of epithelial ovarian cancer. Antiangiogenic agent is the first approved targeted agent in ovarian cancer. Anti-angiogenic agents mainly include agents target VEGF/VEGFR pathway, such as bevacizumab and agents target receptor tyrosine kinase, and non-VEGF/VEGFR targets of angiogenesis. Antiangiogenic agents demonstrate certain effects in ovarian cancer treatment either as monotherapy or combined with chemotherapy. Unfortunately, antiangiogenic agents, such as bevacizumab, integrated into the ovarian cancer treatment paradigm do not increase cures. Thus, the benefits of anti-angiogenic agents must be carefully weighed against the cost and associated toxicities. Antiangiogenic agents drug resistance and short of predictive biomarkers are main obstacles in ovarian cancer treatment. A combination of poly (ADP-ribose) polymerase inhibitors or immune checkpoint inhibitors might be great strategies to overcome resistance as well as enhance anti-tumor activity of anti-angiogenic drugs. Predictive biomarkers of antiangiogenic agents are in urgent need.

Development and Validation of an Immune-Related Prognostic Signature in Cervical Cancer.

Background: Cervical cancer is the fourth most frequent gynecological malignancy across the world. Immunotherapies have proved to improve prognosis of cervical cancer. However, few studies on immune-related prognostic signature had been reported in cervical cancer. Methods: Raw data and clinical information of cervical cancer samples were downloaded from TCGA and UCSC Xena website. Immunophenoscore of immune infiltration cells in cervical cancer samples was calculated through the ssGSEA method using GSVA package. WGCNA, Cox regression analysis, LASSO analysis, and GSEA analysis were performed to classify cervical cancer prognosis and explore the biological signaling pathway. Results: There were eight immune infiltration cells associated with prognosis of cervical cancer. Through WGCNA, 153 genes from 402 immune-related genes were significantly correlated with prognosis of cervical cancer. A 15-gene signature demonstrated powerful predictive ability in prognosis of cervical cancer. GSEA analysis showed multiple signaling pathways containing Programmed cell death ligand-1 (PD-L1) expression and PD-1 checkpoint pathway differences between high-risk and low-risk groups. Furthermore, the 15-gene signature was associated with multiple immune cells and immune infiltration in tumor microenvironment. Conclusion: The 15-gene signature is an effective potential prognostic classifier in the immunotherapies and surveillance of cervical cancer.

Identification of hub genes in key hallmarks of ovarian cancer via bioinformatics analysis.

BACKGROUND: Ovarian cancer is one of the most lethal malignant gynecologic tumors worldwide. We aimed to identify critical hallmarks of the surface epithelium between normal ovaries and serous ovarian carcinomas and then obtain the hub genes associated with these critical hallmarks. METHODS: We chose GSE36668, GSE54388 and GSE69428 as data sources and then determined the common gene sets through gene set enrichment analysis (GSEA) to explore essential hallmarks and hub genes driving normal ovarian cells to evolve progressively into a neoplastic state. The differentially expressed genes (DEGs) extracted separately in each gene set were analyzed again through the Metascape website. Kaplan-Meier plotter was used to obtain significant prognostic information. The hub genes were obtained through protein-protein interaction (PPI) network by Cytoscape. Hub genes were confirmed to have higher mRNA and protein expression levels in ovarian cancer tissues than in normal tissues through public databases [Gene Expression Profiling Interactive Analysis (GEPIA) and The Human Protein Atlas]. Correlation analysis of six hub genes showed a strong correlation via R. RESULTS: We obtained 11 common hallmarks from GSEA of the three mentioned datasets and 22 hub genes that showed a significant association with poor survival. CONCLUSIONS: Not only the gene sets enriched by GSEA but also the hub genes extracted by the PPI network indicate that the most fundamental trait of ovarian cancer cells involves their ability to sustain chronic proliferation.

Parallel Loop Binding Compression Suture, a Modified Procedure for Pernicious Placenta Previa Complicated With Placenta Increta.

Objective: To evaluate the efficacy and safety of parallel loop binding compression suture of the lower uterus during cesarean section in pernicious placenta previa complicated with placenta increta. Methods: This retrospective study was performed in patients with pernicious placenta previa complicated with placenta increta or percreta between November 2014 and December 2020 at the Qilu Hospital of Shandong University. Patients underwent parallel loop binding compression suture surgery were defined as study group, and patients underwent traditional surgery with figure-of-eight sutures as the main hemostatic method were defined as control group. Postpartum hemorrhage was evaluated as the primary outcome. The secondary outcomes included age, gestational weeks, operative time, fetal childbirth time, prevention of hysterectomy, blood transfusion, duration of postoperative catheterization, duration of antibiotic treatment, and postoperative hospitalization (days). Additionally, neonatal outcomes were evaluated. Results: A total of 124 patients were enrolled in the study, including 38 patients receiving parallel loop binding compression suture surgery in the study group, and 86 patients in the control group. With parallel loop binding compression suture, the average operation time was significantly reduced (109.0 ± 33.5 vs. 134.4 ± 54.2 min, p = 0.00), and the volume of blood lost were also decreased (2152.6 ± 1169.4 vs. 2960.5 ± 1963.6 ml, p = 0.02), which correspondingly reduced RBC transfusion (7.2 ± 3.5 vs. 10.3 ± 8.7 units, p = 0.03) and FFP transfusion (552.6 ± 350.3 vs. 968.0 ± 799.8 ml, p = 0.00). The fetal childbirth time was extended (14.1 ± 5.6 vs. 11.0 ± 8.0 min, p = 0.03), however, there was no increase in NICU admission rates (36.9 vs. 34.9%, p = 0.83). Except for one premature infant (32 weeks) death in the control group, all infants at our hospital were safely discharged after treatment. Conclusion: Parallel loop binding compression suture is an effective, swift, practical, and safe method to reduce postpartum bleeding in women with pernicious placenta previa, complicated with placenta increta. Besides, it has no adverse effects on newborns.

Effects of Neoadjuvant Chemotherapy in Ovarian Cancer Patients With Different Germline BRCA1/2 Mutational Status: A Retrospective Cohort Study.

BACKGROUND: Whether neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) against primary debulking surgery (PDS) has a differential effect on prognosis due to Breast Cancer Susceptibility Genes (BRCA)1/2 mutations has not been confirmed by current studies. METHODS: All patients included in this retrospective study were admitted to Qilu Hospital of Shandong University between January 2009 and June 2020, and germline BRCA1/2 mutation were tested. Patients in stage IIIB, IIIC, and IV, re-staged by International Federation of Gynecology and Obstetrics (FIGO) 2014, were selected for analysis. All patients with NAC received 1-5 cycles of platinum-containing (carboplatin, cisplatin, or nedaplatin) chemotherapy. Patients who received maintenance therapy after chemotherapy were not eligible for this study. All relevant medical records were collected. RESULTS: A total of 322 patients were enrolled, including 112 patients with BRCA1/2 mutations (BRCAmut), and 210 patients with BRCA1/2 wild-type (BRCAwt). In the two groups, 40 BRCAmut patients (35.7%) and 69 BRCAwt patients (32.9%) received NAC. The progression-free survival (PFS) of BRCAmut patients was significantly reduced after NAC (median: 14.9 vs. 18.5 months; p=0.023); however, there was no difference in overall survival (OS) (median: 75.1 vs. 72.8 months; p=0.798). Whether BRCAwt patients received NAC had no significant effect on PFS (median: 13.5 vs. 16.0 months; p=0.780) or OS (median: 54.0 vs. 56.4 months; p=0.323). Multivariate analyses in BRCAmut patients showed that the predictors of prolonged PFS were PDS (p=0.001), the absence of residual lesions (p=0.012), and FIGO III stage (p=0.020); Besides, PARP inhibitor was the independent predictor for prolonged OS in BRCAmut patients (p=0.000), for BRCAwt patients, the absence of residual lesions (p=0.041) and history of PARP inhibitors (p=0.000) were beneficial factors for OS prolongation. CONCLUSIONS: For ovarian cancer patients with FIGO IIIB, IIIC, and IV, NAC-IDS did not adversely affect survival outcomes due to different BRCA1/2 germline mutational status.

Overexpression of PRC1 indicates a poor prognosis in ovarian cancer.

Protein regulator of cytokinesis­1 (PRC1) is a microtubule­associated factor involved in cytokinesis. Recent studies have indicated that PRC1 overexpression is involved in tumorigenesis in multiple types of human cancer. However, the expression, biological functions and the prognostic significance of PRC1 in ovarian cancer have not yet been clarified. In this study, it was confirmed that the PRC1 mRNA and protein expression levels were upregulated in high­grade serous ovarian carcinoma (HGSOC) tissues, particularly in patients without breast cancer susceptibility gene (BRCA) pathogenic mutations. PRC1 overexpression contributed to drug resistance, tumor recurrence and a poor prognosis. The findings also indicated that PRC1 knockdown decreased the proliferation, metastasis and multidrug resistance of ovarian cancer cells in vitro. It was also demonstrated that forkhead box protein M1 (FOXM1) regulated the mRNA and protein expression of PRC1. Dual­luciferase reporter assay and rescue assay confirmed that PRC1 was a direct crucial downstream target of FOXM1. On the whole, the findings of this study confirmed that PRC1 was a major prognostic factor of HGSOC and a promising therapeutic biomarker for the treatment of ovarian cancer.

γ-Glutamyl cyclotransferase contributes to endometrial carcinoma malignant progression and upregulation of PD-L1 expression during activation of epithelial-mesenchymal transition.

Recent increases in the incidence of endometrial carcinoma represent a significant risk to women's health. We found that γ-glutamyl cyclotransferase (GGCT) was significantly up-regulated in endometrial carcinoma tissues and cells, which suggested that it may be a potential target for treatment of endometrial carcinoma. Furthermore, the impact of GGCT on proliferation, migration, and invasion of endometrial carcinoma has been demonstrated in vitro and in vivo using GGCT silencing and overexpression techniques. In addition, the epithelial-mesenchymal transition (EMT) was significantly inhibited in response to GGCT knockdown, which indicated that GGCT may contribute endometrial carcinoma malignancy during activation of the EMT. We also found that GGCT regulated PD-L1 expression during EMT activation. Furthermore, co-culture of endometrial carcinoma cells with CD8+ T lymphocytes showed that downregulation of PD-L1 expression following GGCT knockdown contributed to the killing activity of CD8+ T lymphocytes on endometrial carcinoma cells. In conclusion, our study showed that GGCT contributed to malignant progression and upregulation of PD-L1 expression of endometrial carcinoma, and may be a potential target for treatment of endometrial carcinoma.

Peritoneal cancer after bilateral mastectomy, hysterectomy, and bilateral salpingo-oophorectomy with a poor prognosis: A case report and review of the literature.

BACKGROUND: Primary peritoneal cancer (PPC) patients with BRCA mutations have a good prognosis; however, for patients with BRCA mutations who are diagnosed with PPC after prophylactic salpingo-oophorectomy (PSO), the prognosis is poor, and survival information is scarce. CASE SUMMARY: We treated a 56-year-old woman with PPC after bilateral mastectomy, hysterectomy, and bilateral salpingo-oophorectomy. This patient had primary drug resistance and died 12 mo after the diagnosis of PPC. The genetic test performed on this patient indicated the presence of a germline BRCA1 mutation. We searched the PubMed, Scopus, and Cochrane databases and extracted studies of patients with BRCA mutations who developed PPC after PSO. After a detailed literature search, we found 30 cases, 7 of which had a history of breast cancer, 14 of which had no history of breast cancer, and 9 of which had an unknown history. The average age of PSO patients was 48.86 years old (range, 31-64 years). The average time interval between the diagnosis of PPC and preventive surgery was 61.03 mo (range, 12-292 mo). The 2-year survival rate for this patient population was 78.26% (18/23), the 3-year survival rate was 50.00% (9/18), and the 5-year survival rate was 6.25% (1/16). CONCLUSION: Patients with BRCA mutations who are diagnosed with PPC after preventative surgery have a poor prognosis. Prevention measures and treatments for these patients need more attention.

High expression of HMBOX1 contributes to poor prognosis of gastric cancer by promoting cell proliferation and migration.

Homeobox-containing 1 (HMBOX1) has been reported to be associated with biological characteristics of some tumors, but its roles in gastric cancer have never been reported. In the present study, we found that HMBOX1 expression was significantly upregulated in gastric cancer tissues and cell lines and correlated with the TNM stage, lymph-node metastatic and the overall survival (OS) of patients of gastric cancer. The overexpression of HMBOX1 in gastric cancer cells enhanced cell proliferation by accelerating cell cycle, induced cell migration. In contrast, silencing HMBOX1 inhibited these processes. And the expression of HMBOX1 was related with the expression of vascular endothelial growth factor receptor (VEGFR), transforming growth factor-ß (TGF-ß) and CD133. What's more, we found that the expression of CD133 had a significantly positive correlation with HMBOX1 in gastric cancer tissues, and the co-expression of HMBOX1 and CD133 was significantly correlated with poor prognosis of gastric cancer patients, especially for patients at III and IV stage. In conclusion, HMBOX1 was upregulated in gastric cancer and correlated with gastric cancer cell proliferation and migration. Moreover, HMBOX1 combined CD133 might be useful to predict survival of patients with advanced gastric cancer.

FOXD1 is targeted by miR-30a-5p and miR-200a-5p and suppresses the proliferation of human ovarian carcinoma cells by promoting p21 expression in a p53-independent manner.

High-grade serous ovarian carcinoma (HGSOC) accounts for the highest number of deaths among patients with epithelial ovarian cancer. However, the molecular mechanisms underlying HGSOC tumorigenesis are currently unclear. In the present study, a lentiviral expression system was employed to manipulate forkhead box D1 (FOXD1) expression in ovarian cancer cells. Immunohistochemical staining was used to examine the expression of FOXD1 in tissue samples. Clonogenic and MTT assays were employed to evaluate cell proliferation, and flow cytometry was applied for cell cycle analysis. Dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine the role of FOXD1 in regulating p21 expression. The results demonstrated that FOXD1 expression was downregulated in HGSOC, and high expression levels of FOXD1 were found to be a predictor of good prognosis. FOXD1 significantly inhibited the proliferation of human ovarian cancer cells and induced cell cycle arrest at G1 phase in vitro. In addition, exogenous FOXD1 expression inhibited ovarian cancer cell growth in vivo. Furthermore, microRNA (miR)-30a-5p and miR-200a-5p were observed to be upregulated in HGSOC, and function as direct negative regulators of FOXD1 by targeting its 3'-untranslated region. The present study also revealed that FOXD1 promotes p21 expression in a p53-independent manner. In conclusion, the results of the present study indicate a direct association between FOXD1 and p21 that may be mediated by miR-30a-5p and miR-200a-5p. The authors hypothesize that FOXD1 may serve as a biomarker or therapeutic target in HGSOC.

Combination of TP53 and AGR3 to distinguish ovarian high-grade serous carcinoma from low-grade serous carcinoma.

Ovarian high-grade serous carcinoma (HGSC) and low-grade serous carcinoma (LGSC) are distinct gynecologic neoplasms with diverse pathogenesis and characteristic features. They respond differently to same modalities of treatment protocol and have dissimilar prognosis. Thus, it is essential to obtain accurate differential diagnosis of HGSC and LGSC prior to clinical treatment. In the present study, mRNA expression profiles were generated from 5 HGSC and 6 LGSC specimen using HTSeq, and 699 differentially expressed genes (>2-fold difference) were identified using the DESeq R package. Dendrograms produced by unsupervised hierarchical clustering completely distinguished HGSC from LGSC. Among differentially expressed genes between HGSC and LGSC, anterior gradient homolog 3 (AGR3) was highly upregulated in LGSC compared to HGSC, which was validated by reverse transcription­quantitative polymerase chain reaction and western blotting. Then, anti­tumor protein 53 (TP53) and anti-AGR3 immunohistochemistry were performed on 145 HGSC and 30 LGSC samples. Consistent with previous studies, abnormal expression of TP53 (0 or ≥75% positive expression) was observed in 87.6% of HGSC and 13.3% of LGSC samples. Positive staining of AGR3 had a sensitivity of 80.0% and specificity of 89.7% for LGSC. TP53 and AGR3 were both efficient in distinguishing HGSC from LGSC (P<0.001). Receiver operating characteristic analysis revealed a similar area under the curve for AGR3 (0.848) and TP53 (0.871). Through combination of the two markers (TP53 wild­type pattern and AGR3­positive expression), the accuracy of differential diagnosis was up to 93.1%. These findings provide compelling evidence that differential diagnosis of HGSC and LGSC can be improved by combined application of these two markers on the basis of conventional histopathological diagnosis.