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.

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.

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.

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.

Clinicopathological factors and prognosis analysis of 39 cases of non-gestational ovarian choriocarcinoma.

PURPOSE: Non-gestational ovarian choriocarcinoma (NGOC) is a rare malignant germ cell tumor. Through literature review and cases collection, we aim to analyze prognostic factors for NGOC and summarize its clinicopathological characteristics to guide the individualized treatment. METHODS: We searched PubMed database, Cochrane library, and Google Scholar for cases published between January 1, 1967 and July 31, 2018 using various search terms. We retrieved patients' clinicopathological characteristics, treatment, and prognosis information from included studies. These patients were divided into two groups: died (case group) or alive (control group) group. We summarized and compared their clinical (age, symptoms, R0 resection, serum HCG levels, chemotherapy regimen) and pathological (pure vs non-pure type, tumor size, tumor location, metastasis sites, stage) features by statistical analysis. RESULTS: Only 39 patients were retrieved from 36 studies in total. The median age was 30 years (range 12- to 65-years old). The peak incidence was in the adolescent age 12-25 years. Median follow-up was 20.3 months (range 1-84 months). 9 (23%) patients died; 24 (62%) patients were alive; 6 (15%) were lost to follow-up. Upon univariate analysis, we found age had a poor impact on overall survival (OS) in NGOC, HR - 0.057, 95% CI - 0.111 to - 0.004. Pure type NGOC has a better OS than mixed type, HR - 2.621, 95% CI - 4.577 to - 0.666. R0 resection is a good prognostic factor for OS, HR 2.967, 95% CI 0.709-5.224. CONCLUSION: Clinicians should try to achieve R0 resection to improve the prognosis for NGOC patients even among advanced patients.

miRNA-301b-3p accelerates migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis.

High-grade ovarian serous carcinoma (HGS-OvCa), a type of ovarian cancer with poor prognosis due to distant metastasis, is urgently in need of new therapeutic targets. microRNAs (miRNAs), a class of small noncoding RNAs, perform significant roles in tumor progression. Mounting evidence has revealed the aberrant expression of miRNA in various cancers, one of which is HGS-OvCa. Present study planned to investigate that miRNA-301b-3p accelerates migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis. Upregulation of miR-301b-3p was uncovered in HGS-OvCa tissues and cell lines, and was identified to be associated with metastasis. The Kaplan-Meier analysis confirmed the association of miR-301b-3p with poor prognosis of HGS-OvCa patients. Transwell assay validated the oncogenic effect of miR-301b-3p on migration and invasion of HGS-OvCa cells. Cytoplasmic polyadenylation element binding protein 3 (CPEB3) was then identified as a target of miR-301b-3p. It was also discovered that CPEB3 was downregulated in HGS-OvCa tissues and cell lines. The Spearman correlation curve presented the negative correlation of CPEB3 expression with miR-301b-3p. Furthermore, rescue assays proved that miRNA-301b-3p regulated the invasion and migration through CPEB3. Western blot and qRT-PCR analysis showed that miRNA-301b-3p induced epidermal growth factor receptor and downstream metastasis-related proteins, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2), through CPEB3. To be concluded, these results indicated that miRNA-301b-3p accelerated migration and invasion of high-grade ovarian serous tumor via targeting CPEB3/EGFR axis.

ROR2 induces cell apoptosis via activating IRE1α/JNK/CHOP pathway in high-grade serous ovarian carcinoma in vitro and in vivo.

BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal cancer in female genital tumors. New disease markers and novel therapeutic strategies are urgent to identify considering the current status of treatment. Receptor tyrosine kinases family plays critical roles in embryo development and disease progression. However, ambivalent research conclusions of ROR2 make its role in tumor confused and the underlying mechanism is far from being understood. In this study, we sought to clarify the effects of ROR2 on high-grade serous ovarian carcinoma (HGSOC) cells and reveal the mechanism. METHODS: Immunohistochemistry assay and western-blot assay were used to detect proteins expression. ROR2 overexpression adenovirus and Lentivirus were used to create ROR2 overexpression model in vitro and in vivo, respectively. MTT assay, colony formation assay and transwell assay were used to measure the proliferation, invasion and migration ability of cancer cells. Flow cytometry assay was used to detect cell apoptosis rate. Whole transcriptome analysis was used to explore the differentially expressed genes between ROR2 overexpression group and negative control group. SiRNA targeted IRE1α was used to knockdown IRE1α. Kira6 was used to inhibit phosphorylation of IRE1α. RESULTS: Expression of ROR2 was significantly lower in HGSOC tissues compared to normal fallopian tube epithelium or ovarian surface epithelium tissues. In HGSOC cohort, patients with advanced stages or positive lymph nodes were prone to express lower ROR2. Overexpression of ROR2 could repress the proliferation of HGSOC cells and induce cell apoptosis. RNA sequencing analysis indicated that ROR2 overexpression could induce unfold protein response. The results were also confirmed by upregulation of BIP and phosphorylated IRE1α. Furthermore, pro-death factors like CHOP, phosphorylated JNK and phosphorylated c-Jun were also upregulated. IRE1α knockdown or Kira6 treatment could reverse the apoptosis induced by ROR2 overexpression. Finally, tumor xenograft experiment showed ROR2 overexpression could significantly repress the growth rate and volume of transplanted tumors. CONCLUSIONS: Taken together, ROR2 downregulation was associated with HGSOC development and progression. ROR2 overexpression could repress cell proliferation and induce cell apoptosis in HGSOC cells. And the underlying mechanism might be the activation of IRE1α/JNK/CHOP pathway induced by ROR2.

Primary yolk sac tumor of the endometrium: a case report and review of the literatures.

PURPOSE: Yolk sac tumor (YST) is a malignant tumor derived from germ cells and usually occurs in the gonads. Extra-gonadal YST is most commonly seen in the vagina of children, but rarely in the cervix, vulva and endometrium. Primary YST of endometrium was extremely rare, standard treatment was still controversial and no guideline was established so far. The aim of the present study was to provide a comprehensive understanding and systematic thought for the management of primary YST of endometrium. METHODS: A systematic research of the literature was conducted in Scopus, PubMed database and Cochrane Library, including case reports and case series. We summarized clinical characteristics, treatments and prognosis of all collected cases. We collected data regarding patients, serum AFP level, initial symptoms, surgical information, postoperative chemotherapy and radiotherapy. A new case was also discussed. RESULTS: We found only 26 cases have been reported previously. We reported a new case of primary endometrial YST in a 27-year-old woman, and in this case, we creatively performed bilaterally ovarian preservation and used DC (docetaxel and carboplatin) regimen of postoperative chemotherapy, we achieved a relatively good prognosis during the follow-up period of 14 months. CONCLUSION: Primary YST of endometrium, kind of highly malignant germ cell tumors, was extremely rare, of which initial symptom is usually abnormal vaginal bleeding. Standard treatment was still controversial and no guideline was established so far. Surgery combining with postoperative chemotherapy was considered effective for treatment of primary endometrial YST. Decision on whether to preserve ovaries in young patient with early stage needs careful consideration, comprehensive preoperative assessment and full communication. Intraoperative biopsy and strict postoperative follow-up are recommended. However, standard chemotherapy regimen and feasibility of postoperative radiotherapy remains to be discussed.

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.

miRNA-34a decreases ovarian cancer cell proliferation and chemoresistance by targeting HDAC1.

This study aimed to explore the roles of miRNA-34a (miR-34a) in ovarian cancer (OC) cells and uncover possible mechanisms. The proliferation of OC cells was measured with an MTT assay and soft agar colony formation assay. TargetScan analysis, real-time PCR, and a luciferase reporter assay were used to demonstrate the downstream target of miR-34a in OC cells. HDAC1 expression levels were detected by immunoblot analysis. miR-34a inhibited the proliferation of SKOV3 and OVCA433 cells and enhanced cisplatin sensitivity in cisplatin-resistant SKOV3cp cells. The results of TargetScan analysis, real-time PCR, and luciferase reporter assay confirmed that miR-34a downregulated HDAC1 expression by directly targeting the 3'-UTR of HDAC1 mRNA. The overexpression of HDAC1 decreased cisplatin sensitivity and promoted proliferation in OC cells. MTT assay and soft agar colony formation assay showed that HDAC1 overexpression blocked the suppressive effects of miR-34a on SKOV3 cell proliferation. In addition, treatment with the miR-34a mimic partially recovered the cisplatin sensitivity of SKOV3cp cells, whereas HDAC1 overexpression blocked the above phenomena caused by treatment with the miR-34a mimic. miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.

Hypoxia-Inducible Factor 1-α (HIF-1α) Induces Apoptosis of Human Uterosacral Ligament Fibroblasts Through the Death Receptor and Mitochondrial Pathways.

BACKGROUND Hypoxia induces cell apoptosis in the uterosacral ligaments of patients with pelvic organ prolapse by upregulation of hypoxia-inducible factor-1α (HIF-1α). This study aimed to investigate the effects of HIF-1α on human uterosacral ligament fibroblasts (hUSLFs) following treatment with the chemical inducer of hypoxia, cobalt chloride (CoCl2), and to explore the underlying mechanisms. MATERIAL AND METHODS Ten women who underwent hysterectomy for benign disease provided uterosacral ligament tissue for cell extraction. Following CoCl2 treatment, cell viability of isolated and cultured hUSLFs was evaluated by the MTT assay. JC-1 fluorescence mitochondrial imaging was used to study the change in mitochondrial membrane potential. Cell apoptosis and expression of apoptosis-associated proteins and collagen type I alpha 1 (COL1A1) were measured by flow cytometry, TUNEL and Western blot, respectively. RESULTS Hypoxia increased the expression of HIF-1a and increased cell apoptosis, decreased cell viability and expression levels of COL1A1. The JC-1 assay showed that the mitochondrial membrane potential was reduced and caspase-8, and -9 inhibitors partly reduced hUSLF apoptosis. HIF-1α treatment downregulated the expression of cellular FLICE inhibitory protein (c-FLIP), decoy receptor 2 (DcR2), and the ratio of Bcl-2 to Bax, and upregulated the expression tumor necrosis factor related apoptosis-inducing ligand (TRAIL), death receptor 5 (DR5) or TRAIL-R2, Fas, Bcl-2 interacting protein 3 (BNIP3), and cytochrome C, and increased the activation of caspase-3, caspase-8, and caspase-9, all of which were reversed by knockdown of HIF-1α. CONCLUSIONS HIF-1α significantly induced apoptosis of hUSLFs through both the cell death receptor and the mitochondrial-associated apoptosis pathways.

Risk of parametrial invasion in women with early stage cervical cancer: a meta-analysis.

PURPOSE: To first evaluate the predictive value of lymph-vascular space invasion (LVSI) and pelvic lymph node metastases (LNM) to parametrial invasion (PI) in patients with early stage cervical cancer. METHODS: A systematic search of electronic databases was conducted to identify publications exploring the association between LVSI, LNM, and PI. The following databases were searched: PubMed/Medline and Web of Science. Twenty relevant studies were included. Pooling of results was done based on these studies and a diagnostic meta-analysis was performed. RESULTS: 20 articles and a total of 7373 cases were included in the meta-analysis. 17 studies analyzed the correlation between LVSI and PI and 18 studies evaluated the correlation between LNM and PI. The existence of LVSI accelerated PI with OR being 7.37 (95% CI 5.70-9.54) in fixed-effect model and 7.32 (95% CI 4.65-10.39) in random effects model. LVSI shows high sensitivity of 0.80 and the AUC was 0.82. The existence of LNM accelerated PI. LNM shows the highest specificity of 0.90 and the AUC was 0.77. CONCLUSIONS: Both LVSI and LNM are associated with PI. Conization and lymphadenectomy might be helpful to predict the parametrial status of patients with early stage cervical cancer. In addition, the results of this meta-analysis are helpful for designing further prospective clinical trials.

Prognostic roles of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in ovarian cancer: a meta-analysis of retrospective studies.

PURPOSE: The systemic inflammatory response markers have been reported to be associated with the prognosis of various cancers. We conducted this meta-analysis of retrospective studies to evaluate and identify the prognostic impact of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on ovarian cancer. METHODS: PubMed, EMBASE, and China National Knowledge Infrastructure databases were included to search for eligible studies. The following terms were used: "neutrophil to lymphocyte ratio", "NLR", "platelet to lymphocyte ratio", "PLR", "ovarian cancer", "ovary cancer", "ovarian carcinoma", "ovary carcinoma", "ovarian neoplasm", "ovary neoplasm", "ovarian tumor", and "ovary tumor". The random-effects model was chosen to estimate the pooled HR with 95% CI. Heterogeneity between studies was assessed by Higgins I2 value. The stability and heterogeneity of studies were analyzed by sensitivity analysis. Publication bias was examined by Egger's test and Begg's test with the funnel plots. RESULTS: 13 studies consisting of 3467 patients were considered for meta-analysis. We found that the high NLR had a poor prognostic impact on OS and PFS in ovarian cancer, with a pooled HR 1.70, 95% CI 1.35-2.15 and HR 1.77, 95% CI 1.48-2.12, respectively. Similarly, the results showed the high PLR adversely affected OS and PFS in ovarian cancer, with a pooled HR 2.05, 95% CI 1.70-2.48 and HR 1.85, 95% CI 1.53-2.25, respectively. CONCLUSION: In conclusion, we found that both NLR and PLR had an unfavorable impact on PFS and OS of patients with ovarian cancer. Our meta-analysis supported that NLR/PLR could be effective prognostic predictors of ovarian cancer.

Ectopic repression of receptor tyrosine kinase-like orphan receptor 2 inhibits malignant transformation of ovarian cancer cells by reversing epithelial-mesenchymal transition.

Receptor tyrosine kinase-like orphan receptor 2 is an enzyme-linked receptor which specifically modulates WNT5A signaling and plays an important role in tumorigenesis, invasion, and metastasis; however, the precise role of receptor tyrosine kinase-like orphan receptor 2 in cancer is controversial. The purpose of this study was to investigate the expression and role of receptor tyrosine kinase-like orphan receptor 2 in ovarian carcinoma and clarify the biological functions and interactions of receptor tyrosine kinase-like orphan receptor 2 with non-canonical Wnt pathways in ovarian cancer. The result of the human ovary tissue microarray revealed that the receptor tyrosine kinase-like orphan receptor 2-positive rate increased in malignant epithelial ovarian cancers and was extremely higher in the metastatic tumor tissues, which was also higher than that in the malignant ovarian tumor tissues. In addition, high expression of receptor tyrosine kinase-like orphan receptor 2 was closely related with ovarian cancer grading. The expression of receptor tyrosine kinase-like orphan receptor 2 protein was higher in SKOV3 and A2780 cells than OVCAR3 and 3AO cells. Knockdown of receptor tyrosine kinase-like orphan receptor 2 inhibited ovarian cancer cell proliferation, migration, invasion, and induced morphologic as well as digestive state alterations in stably transfected SKOV3 cells. Detailed study further revealed that silencing of receptor tyrosine kinase-like orphan receptor 2 reversed the epithelial-mesenchymal transition and inhibited non-canonical Wnt signaling. Our findings suggest that receptor tyrosine kinase-like orphan receptor 2 may be an important regulator of epithelial-mesenchymal transition, primarily regulated the non-canonical Wnt signaling pathway in ovarian cancer cells, and may display a promising therapeutic target for ovarian cancer.

MicroRNA-200c Inhibits Epithelial-Mesenchymal Transition by Targeting the BMI-1 Gene Through the Phospho-AKT Pathway in Endometrial Carcinoma Cells In Vitro.

BACKGROUND MicroRNA-200c (miR-200c) is a short non-coding RNA that has a role in tumorigenesis and cancer progression. The aims of this study were to investigate the role of miR-200c in cell migration and epithelial-mesenchymal transition (EMT) in endometrial carcinoma cells in vitro. MATERIAL AND METHODS Potential direct targets of miR-200c were identified through the TargetScan database. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used study the expression of miR-200c in the endometrial carcinoma cell lines, Ishikawa and JEC, in vitro. Cell migration was studied using transwell assays. Expression of the mesenchymal marker, N-cadherin, the epithelial marker, E-cadherin, the transcription factor, Slug, the BMI-1 protein, AKT, and p-AKT were measured using Western blot. Small interfering RNA (siRNA) was used to silence the BMI-1 gene to study the targeting effect. RESULTS Over-expression of miR-200c in Ishikawa and JEC cells resulted in reduced cell migration and proliferation. Western blot showed that overexpression of miR-200c downregulated the expression of the BMI-1 protein, p-AKT, N-cadherin and Slug, and the expression E-cadherin was upregulated; silencing miR-200c reversed these results. Silencing the BMI-1 gene inhibited EMT and suppressed p-AKT in miR-200c-inhibited endometrial carcinoma cells by increasing E-cadherin expression, reducing the expression of N-cadherin and the EMT-associated transcription factor, Slug. CONCLUSIONS In endometrial carcinoma cells in vitro, miR-200c inhibited EMT by targeting the BMI-1 gene through the p-AKT pathway.

Elevated periostin in serum and peritoneal washing fluids as potential biomarkers for endometriosis.

BACKGROUND: To identify the level of periostin in serum and peritoneal washing fluids (PWF) from women with and without endometriosis, as well as to explore the potential of periostin as a biomarker of endometriosis. METHODS: Samples were obtained from 184 women with and without endometriosis. Concentrations of periostin in PWF and blood were measured by enzyme-linked immunosorbent assay. RESULTS: Levels of periostin both in serum and PWF were notably elevated in women with endometriosis in both the proliferative and secretory phase. Combined with dysmenorrhea and infertility, two potential covariates, the serum periostin had a sensitivity of 75.00%, specificity of 65.00%, and area under the curve (AUC) of 0.774, whereas the PWF periostin had a sensitivity of 94.23%, specificity of 90.00%, and AUC of 0.967 for the diagnosis of endometriosis. CONCLUSION: Serum and PWF periostin concentrations may be new potential biomarkers for endometriosis, especially when combined with dysmenorrhea and infertility.

Can postoperative GnRH agonist treatment prevent endometriosis recurrence? A meta-analysis.

PURPOSE: To investigate whether postoperative GnRH agonist (GnRH-a) treatment can prevent endometriosis recurrence. METHODS: This meta-analysis searched PubMed, Embase and Cochrane Library for relevant studies published online before June 2015. Seven randomized controlled trials including 328 patients with postoperative GnRH-a treatment and 394 patients in control group were included in the meta-analysis. In the meta-analysis, the recurrence rate of GnRH-a group compared with control group was evaluated with odds ratio (OR) and its 95 % confidence interval (CI). Heterogeneity, small study effect and publication bias were, respectively, assessed using Higgins I (2), sensitivity analysis and funnel plot. RESULTS: Postoperative GnRH-a treatment for endometriosis (pooled OR = 0.71; 95 % CI 0.52-0.96) was superior to expectant or placebo treatment in prevention of the recurrence. The recurrence rate decreased significantly in patients who received 6 months GnRH-a treatment (pooled OR = 0.59, 95 % CI 0.38-0.90), whereas no significant difference of recurrence rate existed between patients with 3 months post-surgical GnRH-a therapy and the control group (pooled OR = 0.87, 95 % CI 0.56-1.34). No significant heterogeneity and small study effect were found in the meta-analysis. However, publication bias did existed in the present meta-analysis. CONCLUSIONS: Longer-term (6 months) postoperative administration of GnRH-a can decrease the recurrence risk of endometriosis, whereas 3 months duration of GnRH-a therapy makes no significant difference in preventing the recurrence of endometriosis. Therefore, instead of a 3 month therapy, the duration of the postoperative administration should be longer enough (6 months) to prevent the recurrence of endometriosis.

CXCR7 signaling induced epithelial-mesenchymal transition by AKT and ERK pathways in epithelial ovarian carcinomas.

Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis, through which cancer cells acquire an invasion and metastasis capacity. Notably, the chemokine receptor CXCR7 and its ligands CCL19 can also facilitate lymph node metastasis in epithelial ovarian carcinomas. Here, we assumed that CXCR7 might be involved in the EMT process of epithelial ovarian carcinomas. In our study, CXCR7 activation and inhibition in SKOV3 were induced with exogenous CCL19 and CXCR7 small interfering RNA (CXCR7 siRNA), respectively. AKT and ERK protein of CXCR7 pathways as well as biomarkers (vimentin, snail, N-cadherin, and E-cadherin) of EMT were detected using the Western blot. Our results showed that CCL19 can induce AKT and ERK phosphorylation in a dose-dependent fashion; however, CXCR7 siRNA efficaciously suppressed CCL19-induced AKT and ERK phosphorylation in comparison with control siRNA. Importantly, CCL19 alone treatment can upregulate the expression of vimentin, snail, and N-cadherin of SKOV3 and downregulate the expression of E-cadherin. Conversely, knockdown of CXCR7 did not reveal any changes compared with CCL19 and the control. In conclusion, these findings demonstrate that EMT can be regulated by the CCL19/CXCR7 axis in epithelial ovarian carcinomas and then involved in the tumor cell invasion and metastasis process via activation of AKT and ERK pathways. Our study lays a new foundation for the treatment of epithelial ovarian carcinomas through antagonizing CXCR7.

Risk of endometrial polyps in women with endometriosis: a meta-analysis.

BACKGROUND: Endometrial polyps (EP) and endometriosis are both estrogen-dependent overgrowths of the endometrium. Several studies have shown a higher frequency of EP in endometriosis patients when compared with women without endometriosis. Therefore, we performed a meta-analysis to investigate the risk of EP in women with endometriosis. METHODS: This meta-analysis searched for articles published between 1964 and 2014 in PubMed, Embase, and Cochrane Library, as well as in Chinese databases, including CNKI, VIP and Wanfang, regarding the association between endometriosis and EP. Nine cohort studies and one case-control study including 2896 women were included in this meta-analysis. The EP risk was evaluated using relative risk (RR) with a 95% confidence interval (CI). Heterogeneity, small study effect and publication bias were assessed using Higgins I(2), sensitivity analysis and funnel plots, respectively. RESULTS: The risk of EP increased in women with endometriosis compared with those without endometriosis (the pooled RR, 2.81; 95% CI, 2.48-3.18). No significant heterogeneity, small study effect or publication bias was found. The risk of EP slightly increased in women with endometriosis at stages 2-4 compared with those at stage 1 (Pooled effect size: stage 2 versus stage 1, RR, 1.22, 95% CI, 1.04 - 1.42; stage 3 versus stage 1, RR, 1.23, 95% CI, 1.06-1.42; stage 4 versus stage 1, RR, 1.29, 95% CI, 1.11-1.51; stages 2-4 versus stage 1, RR, 1.24, 95% CI, 1.10-1.40); however, no significantly different risk of EP in women with endometriosis existed between the other stages. CONCLUSION: The results suggest that it is important to identify whether patients with endometriosis also have EP and then remove any coexisting EP via hysteroscopy, especially for infertile patients. This process will be clinically helpful to treat endometriosis-related infertility in patients with endometriosis, especially for those with endometriosis that is more serious than stage 1.