RBMS3 Expression and Its Correlation with Clinicopathological Features and Prognosis of Epithelial Ovarian Cancer / 中山大学学报(医学科学版)

ObjectiveTo investigate the expression of RNA binding motif single stranded interacting protein 3 （RBMS3） in epithelial ovarian cancer （EOC） tissues and its relationship with the clinicopathological features and prognosis of EOC. MethodsThe study enrolled the paraffin-embedded tissues from 110 EOC cases and 73 benign epithelial ovarian tumor cases pathologically diagnosed in the first affiliated Hospital of Bengbu Medical College from January 2015 to December 2019. By using anti-RBMS3 polyclonal antibody， the immunohistochemical staining was employed to detect RBMS3 expression in the tissues and then its correlation with the clinicopathological parameters and prognosis of EOC was analyzed. ResultsRBMS3 was expressed in both EOC and benign epithelial ovarian tumor tissues. RBMS3 expression in EOC tissues， significantly related with International Federation of Gynecology and Obstetrics （FIGO） stage， histological grade， CEA levels and survival status， was significantly lower than that in benign epithelial ovarian tumor tissues （P<0.05）. Kaplan–Meier survival curve showed that low RBMS3 expression in EOC patients was correlated with decreased progression-free survival （PFS） and overall survival （OS） （P<0.05）. Univariate analysis showed that RBMS3 expression， FIGO stage， residual lesion size， intestinal metastasis and intraperitoneal implantation were associated with OS of EOC patients （P<0.05）； multivariate analysis showed that low RBMS3 expression and intestinal metastasis were independent risk factors for poor prognosis in EOC patients （P<0.05）. ConclusionsRBMS3 is expressed at low levels in EOC tissues， which is closely related to poor prognosis of EOC patients. RBMS3 may function as a tumor suppressor gene in EOC tissues and can be used as an EOC-independent prognostic marker for targeted therapy against EOC.

Role of magnetic resonance imaging in the differentiation of mucinous ovarian carcinoma and mucinous borderline ovarian tumors

SUMMARY OBJECTIVE: This study was carried out to investigate the differentiation of mucinous borderline ovarian tumor from mucinous ovarian carcinoma using magnetic resonance imaging. METHODS: We evaluated 77 women patients who underwent abdominal magnetic resonance imaging due to pelvic mass. magnetic resonance imaging was reviewed by an experienced radiologist. A total of 70 women patients were included in the study. The magnetic resonance imaging features were retrospectively evaluated and compared between the two pathologies. RESULTS: There was no difference between the two groups in terms of maximum tumor size. Age at diagnosis was 56.29±11.92 in the mucinous ovarian carcinoma group and 44.74±13.60 in the mucinous borderline ovarian tumor group (p<0.05). A significant difference was found between the two groups, and it was observed that mucinous borderline ovarian tumors appeared in the younger age group compared to mucinous ovarian carcinomas. Presence of ascites, peritoneal dissemination, lymphadenopathy, and mural nodules was found significantly more frequently in mucinous ovarian carcinomas than in mucinous borderline ovarian tumors. Honeycomb appearance was found more frequently in mucinous borderline ovarian tumor patients than in mucinous ovarian carcinoma patients. CONCLUSION: magnetic resonance imaging findings of these two pathologies overlapped considerably. Compared with mucinous borderline ovarian tumors, mucinous ovarian carcinomas frequently had mural nodules larger than 5 mm, larger tumor size, peritoneal dissemination, and abnormal ascites.

Estrategias terapéuticas actuales en el tratamiento del cáncer de ovario

Introducción: El cáncer de ovario es uno de los tumores más frecuentes y letales entre las mujeres. Esto se debe a su detección en estados tardíos y al desarrollo de quimiorresistencia a la terapia estándar. El desarrollo de terapias dirigidas contra las propiedades distintivas de las células cancerosas y sus características habilitadoras ha surgido como una alternativa promisoria para el tratamiento de estos tumores. Objetivo: Describir las actuales estrategias terapéuticas dirigidas contra las distintas capacidades de las células tumorales en el tratamiento del cáncer de ovario. Método: Se realizó una búsqueda en las bases de datos ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL´s CLIN, Registro Público Cubano de Ensayos Clínicos, entre enero y abril de 2023. Se seleccionaron 50 artículos referentes al cáncer de ovario y las alternativas para su tratamiento. Desarrollo: Se mencionaron los diversos factores que influyen en la elección de terapias contra el cáncer de ovario. Se describieron las actuales dianas terapéuticas utilizadas en el tratamiento de esta neoplasia, así como el empleo de múltiples fármacos aprobados y en fases de estudio, y las combinaciones sinérgicas de los mismos. Consideraciones finales: Actualmente existen disímiles opciones de tratamiento del cáncer de ovario. A pesar de que la eficacia clínica de los agentes dirigidos todavía está restringida a subtipos moleculares específicos y ningún ensayo ilustra un beneficio en la supervivencia general, son notorios los resultados alcanzados en el desarrollo de fármacos específicamente dirigidos contra la inestabilidad del genoma y angiogénesis sostenida.

Introduction: Ovarian cancer is one of the most common and lethal tumor in women. This happens as a result of late-stage cancer detention and an increased chemoresistance to standard therapy. The current development in therapies to kill the cancer cells and its spread tendencies has emerged as a key alternative to treat tumors. Objective: To describe the current therapeutic strategies lead to confront different capabilities of tumor cells found in the ovarian cancer treatment. Method: A search of literuture was carried out in the following databases ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL's CLIN, Cuban Public Registry of Clinical Trials, from January to April 2023. A total of 50 text concerning ovarian cancer subject and alternative for treatment were selected. Development: The driving factors that promoted the use of ovarian cancer therapies were pointed out. The current therapeutic targets used in the treatment of this neoplasia were described, as well as the use of multiple approved drugs or in process of approval, including the synergistic drug combinations. Final considerations: There are a lot of options currently being implemented in ovarian cancer treatment. Despite clinical efficacy of targeted therapy, it´s presented still restricted to specific molecular subtypes and none of the assays illustrated survival benefit in general; the results obtained in the process of drugs development specifically targeting genome instability and sustained angiogenesis have been remarkable.

Introdução: O câncer de ovário é um dos tumores mais frequentes e letais entre as mulheres. Isso se deve à sua detecção em estágios tardios e ao desenvolvimento de quimiorresistência à terapia padrão. O desenvolvimento de terapias direcionadas contra as propriedades distintas das células cancerígenas e suas características facilitadoras surgiu como uma alternativa promissora para o tratamento desses tumores. Objetivo: Descrever as atuais estratégias terapêuticas dirigidas contra as diferentes capacidades das células tumorais no tratamento do câncer de ovário. Método: Foi realizada uma busca nas bases de dados ScienceDirect, Redalyc, Latindex, ResearchGate, PubMed, Elsevier, ClinicalTrials.gov, SpringerLink, LARVOL's CLIN, Registro Público Cubano de Ensaios Clínicos, entre janeiro e abril de 2023. 50 artigos referentes ao câncer de ovário e as alternativas para o seu tratamento. Desenvolvimento: Foram mencionados os vários fatores que influenciam a escolha das terapias contra o câncer de ovário. Foram descritos os atuais alvos terapêuticos utilizados no tratamento desta neoplasia, bem como o uso de múltiplas drogas aprovadas e em fase de estudo, e suas combinações sinérgicas. Considerações finais: Atualmente existem opções de tratamento dissimilares para o câncer de ovário. Apesar de a eficácia clínica dos agentes direcionados ainda estar restrita a subtipos moleculares específicos e nenhum ensaio mostrar benefício na sobrevida global, são notáveis os resultados alcançados no desenvolvimento de fármacos direcionados especificamente contra a instabilidade do genoma e a angiogênese sustentada.

Effect of the area under the curve of carboplatin dosage on therapeutic efficacy and safety in Chinese patients with epithelial ovarian cancer / 西安交通大学学报(医学版)

【Objective】 To retrospectively analyze the average carboplatin dosage and calculate the area under the curve (AUC) using the Calvert formula in first-line chemotherapy in patients with epithelial ovarian cancer in The First Affiliated Hospital of Xi’an Jiaotong University so as to evaluate the effect of the AUC difference in the Chinese population on therapeutic efficacy and safety. 【Methods】 We enrolled patients who underwent first-line chemotherapy with paclitaxel and carboplatin 3-week regimen in our hospital from January 1, 2012 to January 1, 2022. According to the median of AUC, the patients were divided into high-dose group and low-dose group. The overall response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs) were compared. 【Results】 A total of 153 patients were enrolled in this study and the median AUC of carboplatin was 3.981 (range 2.314-5.446). Only 10.46% patients (16/153) had an AUC above 5. There were 77 patients with the AUC0.05). The ORR in the low-dose group and the high-dose group was 59.74% and 57.89%, respectively, and the DCR was 87.01% and 85.53%, respectively. The median PFS of the two groups was 14 and 15.5 months, respectively, and the median OS was 50 and 55 months, respectively. None of the above outcomes were statistically different between the two groups (P>0.05). The two groups showed significant differences in the incidence of anemia, neutropenia, and thrombocytopenia (P<0.05). The incidence of nausea and vomiting, grade 1-2 diarrhea or constipation, and grade 1-2 fever showed significant differences (P<0.05). In addition, the incidence of dose limiting toxicity (DLT), including grade 4 thrombocytopenia and febrile neutropenia (FN), was significantly increased in the high-dose group (P<0.05). 【Conclusion】 Compared with the recommended AUC 5-6 of carboplatin abroad, the actual carboplatin dosage in the first-line chemotherapy for patients with epithelial ovarian cancer was generally insufficient in our hospital. There was no difference in therapeutic efficacy between the patients with AUC<4 and AUC≥4. However, considering the increased risk of some AEs and DLT in the high-dose group, it is not recommended to increase the carboplatin AUC blindly.

Efficacy and Safety of Anlotinib Combined with PD-1 Blockades for Patients with Advanced Epithelial Ovarian Cancer / 肿瘤防治研究

Objective To investigate the efficacy and safety of anlotinib combined with PD-1 blockades for patients with advanced epithelial ovarian cancer (EOC). Methods A retrospective study was performed, enrolling 33 patients with advanced EOC who failed standard systematic therapy. All patients were administered with anlotinib combined with PD-1 blockades. The efficacy and safety profile were determined during treatment. Results The objective response rate of the 33 patients was 36.4% (95%CI: 20.4%-54.9%) and the disease control rate of the patients was 81.8% (95%CI: 64.5%-90.0%). The median PFS and OS of the 33-patient cohort were 7.6 months (95%CI: 3.1-12.1) and 19.6 months (95%CI: 15.1-24.1), respectively. The most common treatment-related adverse reactions were fatigue (66.7%), nausea and vomiting (54.5%), hypertension (48.5%), and diarrhea (39.4%). Furthermore, multivariate Cox regression analysis indicated that ECOG performance status and FIGO stage were independent factors for predicting the PFS of the combination regimen for patients with advanced EOC. Conclusion Anlotinib combined with PD-1 blockades preliminarily exhibit satisfactory efficacy and tolerable safety profile for patients with advanced EOC.

TIM-3 gene is highly expressed in ephithelial ovarian cancer to promote proliferation and migration of ovarian cancer cells / 南方医科大学学报

OBJECTIVE@#To analyze the expression of immunoglobulin mucin molecule 3 (TIM-3) in epithelial ovarian cancer (EOC) and the effects of TIM-3 knockdown and overexpression on proliferation and migration of ovarian cancer cells.@*METHODS@#We analyzed TIM-3 expression in EOC and normal ovarian tissues using GEPIA database. We also detected TIM-3 expression levels in 82 surgical specimens of EOC and 18 specimens of normal ovarian tissues using immunohistochemistry, and analyzed the correlation of TIM-3 expression with clinicopathological parameters and survival outcomes of the patients. The expression of TIM-3 and Wnt1 mRNA in the tissues were detected using qRT-PCR. We constructed SKOV3 cell models of TIM-3 knockdown and overexpression and examined the changes in proliferation, apoptosis, migration and invasion of the cells using MTT assay, Annexin V-FITC/PI staining, scratch test and Transwell assay. The activity of Wnt/β-catenin pathway in the transfected was detected using dual luciferase reporter assay, and the mRNA levels of TCF-7, TCCFL-2 and CD44 were detected using qPCR. The protein expressions of MMP-9, CD44, Wnt1, β-catenin and E-cad in the transfected cells were detected with Western blotting.@*RESULTS@#The positive expression rate of TIM-3 was significantly higher in EOC tissues than in normal ovarian tissues (P < 0.05). The expression of TIM-3 was significantly correlated with FIGO stage, histological differentiation and lymph node metastasis, and was positively correlated with Wnt1 level (P < 0.05). In SKOV3 cells, TIM-3 knockdown significantly lowered the activity of Wnt/ β-catenin pathway, inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. TIM-3 knockdown significantly down-regulated the mRNA levels of TCF-7, TCFL-2 and CD44 and the protein levels of MMP-9, CD44, Wnt1 and β-catenin, and significantly up-regulated the expression level of E-cad (P < 0.05). Overexpression of TIM-3 caused opposite effects in SKOV3 cells.@*CONCLUSION@#TIM-3 is highly expressed in EOC tissue to promote malignant behaviors of the tumor cells possibly by activating the Wnt/β-catenin signal pathway.

Value of fertility-sparing surgery for young females with epithelial ovarian cancer: a comparative study / Valor de la cirugía de preservación de la fertilidad en mujeres jóvenes con cáncer de ovario epitelial: un estudio comparativo

Resumen OBJETIVO: Comparar la cirugía radical con la cirugía conservadora de la fertilidad en mujeres con cáncer de ovario epitelial en estadio 1A-C con respecto a la tasa de recurrencia y las tasas de supervivencia. Además, evaluar los desenlaces reproductivos y obstétricos para las mujeres con cáncer de ovario epitelial en estadio I tratadas con una conducta conservadora de la fertilidad. PACIENTES Y MÉTODOS: Estudio prospectivo efectuado en pacientes con cáncer de ovario epitelial, estadio I, con edad ≤ 40 años. A las pacientes del grupo de preservación de la fertilidad se les practicó salpingooforectomía del lado del ovario afectado y una biopsia por incisión o escisión en cuña del ovario contralateral. A las pacientes del grupo de cirugía radical se les practicó la histerectomía total y salpingooforectomía bilateral. Para evaluar los desenlaces reproductivos y oncológicos se dio seguimiento a todas las pacientes durante cinco años. RESULTADOS: Se estudiaron 60 pacientes; las del grupo de cirugía de preservación de la fertilidad eran significativamente más jóvenes (30 ± 4 en comparación con 35 ± 5) (p < 0.001), el tamaño de sus tumores era más pequeño 3.4 ± 1.3 en comparación con 6.0 ± 2,6 (p < 0.001), de menor grado (p < 0.001). = 0.011), estadio más precoz (p < 0.001) y con más histología mucinosa que las pacientes del grupo de cirugía radical. No hubo diferencias estadísticamente significativas entre ambos grupos en cuanto a la recurrencia tumoral o las tasas de supervivencia. De 25 pacientes operadas para preservación de la fertilidad 18 de 25 intentaron quedar embarazadas. Se registraron 15 de 18 embarazos, incluidos 13 nacidos vivos, 1 aborto espontáneo y 1 muerte fetal intrauterina. CONCLUSIÓN: La cirugía conservadora de la fertilidad podría ser una alternativa adecuada a la cirugía radical para mujeres jóvenes con cáncer epitelial de ovario en estadio I.

Abstract OBJECTIVE: In the current study, we aimed to compare between radical surgery and fertility saving surgery in females with stage 1A-C EOC regarding recurrence rate and patients survival rates in addition to evaluating reproductive and obstetric outcomes for stage I EOC females who were managed by fertility saving surgery. PATIENTS AND METHODS: We prospectively identified 60 patients diagnosed with stage I EOC aged ≤ 40 years. Patients in the fertility-preservation group underwent salpingo-oophorectomy on the side of the affected ovary in addition to incisional biopsy or wedge excision of the ovary on the other side. Patients in the radical surgery group underwent total hysterectomy and bilateral salpingo-oophorectomy. We followed up all patients for 5 years to assess their reproductive and oncological outcomes. RESULTS: Patients in the fertility preservation surgery group were significantly younger (30 ± 4 versus 35 ± 5) (p < 0.001), their tumor sizes were smaller 3.4 ± 1.3 versus 6.0 ± 2.6 (p < 0.001), of lower grade (p = 0.011), earlier stage (p < 0.001) and has more mucinous histology than patients in the radical surgery group. There were no statistically significant differences between both groups regarding tumor recurrence or survival rates. Of 25 patients underwent fertility preservation surgery, 18/25 (72%) tried to get pregnant. 15/18 (83%) pregnancies were recorded, including 13 live births, 1 miscarriage, and 1 intrauterine fetal death. CONCLUSION: Fertility sparing surgery could be adequate alternative to radical surgery for young females with stage I EOC.

Tumor de células de Sertoli-Leydig: a propósito de un caso y revisión de la literatura reciente / Ovarian Sertoli-Leydig cell tumour: a clinical case and recent basic literature review

INTRODUCCIÓN: Los tumores de células de Sertoli-Leydig son neoplasias de ovario infrecuentes, lo que dificulta su diagnóstico y tratamiento. OBJETIVO: Revisar y sintetizar el manejo actual de los tumores de células de Sertoli-Leydig. MÉTODO: Se realizó una revisión de la literatura reciente sobre tumores de células de Sertoli-Leydig, a propósito de un caso en nuestro centro. RESULTADOS: Los tumores de las células de Sertoli-Leydig son infrecuentes, con mayor incidencia en edades tempranas. Ante una paciente joven con una lesión anexial unilateral y signos de virilización deberán considerarse estos tumores dentro del diagnóstico diferencial. En los estadios iniciales y en pacientes jóvenes podrá plantearse un tratamiento quirúrgico que preserve la fertilidad, y la asociación de tratamiento adyuvante dependerá de la diferenciación y del estadiaje del tumor.

INTRODUCTION: Sertoli-Leydig cell tumors are infrequent ovarian neoplasms, which difficults their diagnosis and treatment. Objective: To review and synthesize the current management of the Sertoli-Leydig cell tumor. METHOD: A review of the recent literature regarding the Sertoli-Leydig cell tumor was carried out, regarding a case in our center. RESULTS: Sertoli-Leydig cell tumors are an infrequent entity, with a higher incidence in early ages. In a young patient with a unilateral adnexal lesion and signs of virilization, these tumors should be considered within the differential diagnosis. In early stages and young patients, a surgical treatment that preserves fertility may be considered, and the association of adjuvant treatment will depend on the differentiation and staging of the tumor.

Role of ATR/CHK1 pathway in the occurrence and development of epithelial ovarian cancer / 中华内分泌外科杂志

Objective:To discuss the role of ataxia telangiectasia and Rad3-related kinase (ATR) /check point kinase 1 (CHK1) signaling pathway in the occurrence and development of epithelial ovarian cancer.Methods:Human epithelial ovarian cancer cells OVCAR3 cells were cultured in vitro, siRNA and VE-822 were used to interfere with ATR in OVCAR3 cells, the effectiveness of interference with ATR expression was detected by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot, the cell proliferation inhibition was detect by CCK-8 method, cell cycle and apoptosis were detected by flow cytometry (FCM) , the mRNA expressions of Caspase-3, B-cell lymphoma-2 (Bcl-2) , Bcl-2-associated X protein (Bax) were detected by qRT-PCR, Western blot was used to detect the expression of ATR/CHK1 pathway related proteins.Results:After siRNA-ATR transfection and VE-822 intervention, compared with those in NC group and siRNA-sc group, the expression level of ATR mRNA [ (1.55±0.12) , (1.51±0.13) , (0.71±0.11) , (0.73±0.12) , (0.49±0.09) ] in OVCAR3 cells in siRNA-ATR group, VE-822 group and siRNA-ATR + VE-822 group was significantly lower ( P<0.05) , the inhibition rate of cell proliferation [ (0.00±0.00) %, (0.00±0.00) %, (32.84±1.08) %, (30.75±1.44) %, (43.90±1.57) %], ratio of G0/G1 phase [ (40.08±2.57) , (36.35±3.44) , (53.28±4.34) , (56.37±5.03) , (70.63±3.81) ], apoptosis rate [ (4.28±0.67) %, (5.35±0.94) %, (23.63±1.13) %, (24.57±1.20) %, (35.86±1.09) %], expression of Caspase-3 and Bax mRNA were significantly higher ( P<0.05) , and the cell proportions in S phase [ (32.93±3.02) , (35.35±2.82) , (25.79±3.61) , (23.74±3.54) , (18.04±2.37) ] and G2/M phase [ (26.99±2.84) , (28.30±2.72) , (20.93±3.01) , (19.98±2.87) , (11.33±2.11) ], Bcl-2 mRNA, ATR, p-CHK1/CHK1, cell division cycle protein 25C (CDC25C) and cyclin B1 protein expression were significantly lower ( P<0.05) . Compared with those in siRNA-ATR group, the expression of ATR mRNA in siRNA-ATR + VE-822 group was further decreased ( P<0.05) , the inhibition rate of cell proliferation, apoptosis, expression of Caspase-3 and Bax mRNA were further increased ( P<0.05) , and the expression of Bcl-2 mRNA, ATR, p-CHK1/CHK1, CDC25C and cyclin B1 protein was decreased continuously ( P<0.05) . Conclusion:ATR/CHK1 signaling pathway is activated during the proliferation of epithelial ovarian cancer OVCAR3 cells. Inhibition of ATR/CHK1 signaling pathway can inhibit the proliferation of epithelial ovarian cancer cells and induce G1/S cell cycle arrest and apoptosis.

Phosphorylation of Cofilin-1 Enhances Paclitaxel Resistance of Epithelial Ovarian Cancer Cells by Inhibiting Apoptosis / 生物医学与环境科学（英文）

Objective@#To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells.@*Methods@#Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1).@*Results@#High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients.@*Conclusion@#The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor.

Loss of 4.1N in epithelial ovarian cancer results in EMT and matrix-detached cell death resistance

Epithelial ovarian cancer (EOC) is one of the leading causes of death from gynecologic cancers and peritoneal dissemination is the major cause of death in patients with EOC. Although the loss of 4.1N is associated with increased risk of malignancy, its association with EOC remains unclear. To explore the underlying mechanism of the loss of 4.1N in constitutive activation of epithelial-mesenchymal transition (EMT) and matrix-detached cell death resistance, we investigated samples from 268 formalin-fixed EOC tissues and performed various in vitro and in vivo assays. We report that the loss of 4.1N correlated with progress in clinical stage, as well as poor survival in EOC patients. The loss of 4.1N induces EMT in adherent EOC cells and its expression inhibits anoikis resistance and EMT by directly binding and accelerating the degradation of 14-3-3 in suspension EOC cells. Furthermore, the loss of 4.1N could increase the rate of entosis, which aggravates cell death resistance in suspension EOC cells. Moreover, xenograft tumors in nude mice also show that the loss of 4.1N can aggravate peritoneal dissemination of EOC cells. Single-agent and combination therapy with a ROCK inhibitor and a 14-3-3 antagonist can reduce tumor spread to varying degrees. Our results not only define the vital role of 4.1N loss in inducing EMT, anoikis resistance, and entosis-induced cell death resistance in EOC, but also suggest that individual or combined application of 4.1N, 14-3-3 antagonists, and entosis inhibitors may be a promising therapeutic approach for the treatment of EOC.

Ezrin Promotes the Proliferation, Migration, and Invasion of Ovarian Cancer Cells / 生物医学与环境科学（英文）

Objective@#The underlying mechanism of Ezrin in ovarian cancer (OVCA) is far from being understood. Therefore, this study aimed to assess the role of Ezrin in OVCA cells (SKOV3 and CaOV3) and investigate the associated molecular mechanisms.@*Methods@#We performed Western blotting, reverse transcription-quantitative polymerase chain reaction, MTT, cell colony, cell wound healing, transwell migration and invasion, RhoA and Rac active pull down assays, and confocal immunofluorescence experiments to evaluate the functions and molecular mechanisms of Ezrin overexpression or knockdown in the proliferation and metastasis of OVCA cells.@*Results@#The ectopic expression of Ezrin significantly increased cell proliferation, invasiveness, and epithelial-mesenchymal transition (EMT) in OVCA cells. By contrast, the knockdown of endogenous Ezrin prevented OVCA cell proliferation, invasiveness, and EMT. Lastly, we observed that Ezrin can positively regulate the active forms of RhoA rather than Rac-1 in OVCA cells, thereby promoting robust stress fiber formation.@*Conclusion@#Our results indicated that Ezrin regulates OVCA cell proliferation and invasiveness by modulating EMT and induces actin stress fiber formation by regulating Rho-GTPase activity, which provides novel insights into the treatment of the OVCA.

Subtype specific biomarkers associated with chemoresistance in epithelial ovarian cancer

In spite of the advent of many high throughput technologies, tumor tissue biomarkers are still the gold standard for diagnosis and prognosis of different malignancies including epithelial ovarian cancer (EOC). EOC is a heterogeneous disease comprised of five major subtypes which show distinct clinicopathological features and therapy response. Acquirement of chemoresistance toward therapy is a major challenge for successful treatment outcome in EOC patients. Several markers have been tested by immunohistochemical method to evaluate their prognostic merit to predict clinical outcome. However, a vast majority of such markers have been assessed for high-grade serous and clear cell ovarian cancer, among all subtypes of EOC. The current review elaborates upon those biomarkers that can potentially predict chemoresistance with subtype specificity.

Role of pelvic and para-aortic lymphadenectomy in epithelial ovarian cancers

Background: Lymphadenectomy in epithelial ovarian cancers has remained a controversial subject. Lack of robust evidence on survival benefits and surgical morbidity associated questions its role in the era of adjuvant chemotherapy. The present study assessed pelvic and para-aortic lymph node removal in epithelial ovarian cancer in Indian women and tried to find clinicopathological correlation of nodal involvement and postoperative implications of lymphadenectomy.Methods: Thirty patients with diagnosis of epithelial ovarian cancer posted for primary debulking surgery were recruited and underwent staging laparotomy along with pelvic and para-aortic lymphadenectomy. Nodal involvement was confirmed on histopathology and various parameters which could predict nodal metastasis were assessed. Patients were followed up for 12 months post-surgery.Results: Nodal yield was ten for pelvic and four for paraaortic nodes. Pelvic node involvement was seen in 26.6% (8/30) of the patients and para-aortic in 15% (3/20) of the patients. Serous histology, higher grade, stage 3 and above, positive peritoneal cytology, omental involvement showed a higher lymph node involvement though not statistically significant. Para-aortic lymphadenectomy was associated with increased operating time, blood loss and longer hospital stay.Conclusions: Lymphadenectomy increases morbidity and decision should be based on predictors of nodal involvement.

Factors associated with surgical morbidity of primary debulking in epithelial ovarian cancer

Efficacy and safety of neoadjuvant chemotherapy versus primary debulking surgery in patients with ovarian cancer: a meta-analysis / 부인종양

OBJECTIVE: Neoadjuvant chemotherapy (NACT) for the treatment of epithelial ovarian cancer (EOC) has remained controversial. This meta-analysis was performed to systematically assess the efficacy and safety of NACT versus primary debulking surgery (PDS) in patients with EOC.METHODS: PubMed, Embase, ClinicalTrials.gov, and Cochrane Library were queried to assess the therapeutic value of NACT versus PDS in EOC. Electronic databases were queried by using the keywords “ovarian cancer/neoplasms”, “primary debulking surgery”, and “neoadjuvant chemotherapy”.RESULTS: The available trials were pooled, and hazard ratios (HRs), relative risk ratios (RRs) and associated 95% confidence intervals (95% CIs) were determined. Sixteen trials involving 57,450 participants with EOC (NACT, 9,475; PDS, 47,975) were evaluated. We found that NACT resulted in markedly decreased overall survival than PDS in patients with EOC (HR=1.30; 95% CI=1.13–1.49; heterogeneity: p<0.001, ²=82.7%). Furthermore, our results demonstrated that the NACT group displayed increased completeness of debulking removal (RR=1.69, 95% CI=1.32–2.17; heterogeneity: p<0.001, ²=81.9%), and reduced risk of postsurgical death (RR=0.18, 95% CI=0.06–0.51; heterogeneity: p=0.698, ²=0%) and major infection (RR=0.29, 95% CI=0.17–0.51; heterogeneity: p=0.777, ²=0%) compared with patients administered PDS.CONCLUSIONS: This meta-analysis indicated that NACT results in increased completeness of debulking removal, and reduced risk of postsurgical death and major infection compared with PDS, while PDS is associated with improved survival in comparison with NACT in EOC patients.TRIAL REGISTRATION: PROSPERO Identifier: CRD42019120625

miR-139-5p inhibits proliferation and invasion of epithelial ovarian cancer cells by targeting Notch1 / 中国肿瘤生物治疗杂志

@# Objective: To explore the action mechanism of miR-139-5p inhibiting proliferation and invasion of epithelial ovarian cancer (EOC) cells by targetedly regulatingNotch1.Methods: A total of 24 pairs of EOC tissues and its corresponding para-cancerous tissues from patients, who underwent surgical resection in the DepartmentofGynecology,Nanyang Central Hospital of Henan Province, were collected for this study; in addition, human ovarian cancer cell lines (SKOV3, ES2, HEY-T30) and human ovarian epithelial cell line IOSE80 were also collected. Real-time quantitative PCR (qPCR) was applied to detectmRNAexpressionofmiR-139-5pandNotch1 in EOC tissues and cell lines. The miR-139-5p over-expression vector and recombinant plasmid pLV-Notch1 were transfected into SKOV3 cells. Blank control group (Ctrl group) and negative control group (NC group) were set up. Dual luciferase reporter gene assay was applied to verify the targeting relationship between miR-139-5p and Notch1 3'-UTR. CCK-8, Transwell and Scratch healing experiments were applied to detect cell proliferationinvasionandmigration, respectively. Western blotting was applied to detect expressions of proliferation and migration related proteins in cells. Results: Compared with para-cancerous tissues and IOSE80 cells, the expression of miR-139-5p was significantly decreased in EOC tissues and cell lines, while the expression of Notch1 mRNA was significantly increased (all P<0.01). The results of Dual luciferase reporter showed that Notch1 was the downstream target gene of miR-139-5p. Compared with NC group, cell proliferation, invasion and migration ability, expression levels of Notch1, NICD, Cyclin D1, Cyclin A1, Snail1, β-catenin and N-cadherin were all significantly decreased on 3 d in miR-139-5p mimic group (all P<0.01), while expression of E-cadherin was significantly increased (P<0.01); meanwhile, over-expression of Notch1 could reverse the inhibitory effect of miR-1395p on proliferation, invasion and migration of SKOV3 cells. Conclusion: miR-139-5p can targetedly regulate Notch1 to inhibit proliferation, invasion and migration of EOC cells, which may be related to its down-regulation of NICD, Cyclin D1, Cyclin A1, Snail1, βcatenin and N-cadherin, and up-regulation of E-cadherin.

A Single-Center, Retrospective Study of Bevacizumab-Containing Neoadjuvant Chemotherapy followed by Interval Debulking Surgery for Ovarian Cancer

PURPOSE: We evaluated whether adding bevacizumab to current platinum-based chemotherapy could improve clinical outcomes without affecting safety.MATERIALS AND METHODS: We retrospectively reviewed medical records of patients with pathologically confirmed ovarian cancer who received neoadjuvant chemotherapy (NAC) at Yonsei Cancer Hospital. We divided the patients into groups based on the use of bevacizumab for NAC (CP group: carboplatin+paclitaxel vs. BCP group: bevacizumab+carboplatin+paclitaxel) and compared patient characteristics, responses to NAC, and surgical and survival outcomes between the two groups. Overall, 88 patients in the CP group and 16 patients in the BCP group received NAC. The primary endpoint was survival outcomes. Complete resection rate after interval debulking surgery (IDS), cancer antigen 125 (CA-125) normalization after NAC, and chemotherapy response score were secondary endpoints.RESULTS: After NAC treatment, all patients underwent IDS. There were no significant differences in adverse events during NAC or postoperative complications between the two groups (p=0.293 and p=0.485, respectively). There were also no significant differences in CA-125 normalization after NAC (42.0% vs. 43.8%, p=0.899) or complete resection rate after IDS (47.7% vs. 56.3%, p=0.530). However, although the BCP group did not show longer overall survival (OS) (log-rank p=0.854), they had significantly longer progression-free survival (PFS) than the CP group (log-rank p=0.048).CONCLUSION: Bevacizumab-containing NAC might be safe and provide longer PFS than chemotherapy alone in patients with advanced ovarian cancer. However, further study is necessary to investigate the impact of bevacizumab-containing NAC on OS.

The Impact of IONPs and PBNPs Nanoparticles in Regulating Stemness of Ovarian Carcinoma Cells / 中国药学杂志

OBJECTIVE: To study the effects of iron oxide nanoparticles (IONPs) and prussian blue nanoparticles (PBNPs) on the stemness of epithelial ovarian cancer (EOC) cell lines, which may provide experimental basis and reference significance for the application of nanoparticles in the treatment of EOC. METHODS: SKOV3 and HO8910 cell lines were treated with IONPs and PBNPs respectively, then the drug-resistant genes in mRNA and protein levels were detected by RT-PCR and Western blot. The change of cell proliferation ability were detected by cell proliferation and clone formation experiments, and the expression of surface stemness-related molecules were detected by flow cytometer. RESULTS: The expression of ABCG2 and ALDH1A1 were both down regulated in SKOV3 and HO8910 cell lines treated with IONPs and PBNPs, respectively, while IONPs decreased the CD44+CD117+ subpopulation, and PBNPs increased the CD44+CD117+ subpopulation. Compared with the control cells, the proliferation of SKOV3 cells treated with IONPs and PBNPs were significantly reduced, however, there were no effects on HO8910 cell's proliferation after the cells treated with PBNPs. CONCLUSION: Drug-resistance genes and stem cell subpopulation of EOC SKOV3/HO8910 cell lines treated with IONPs were markedly reduced. However, PBNPs can improve the stem cell subpopulation and promote the cancer stem cell's characteristic of EOC cells but the drug-resistance genes were decreased.

Regulation of HMGA2 and KRAS genes in epithelial ovarian cancer by miRNA hsa-let-7d-3p

Aim of the Study: The purpose of this study was to identify specific circulating microRNAs (miRNAs) and investigate expression level of their target genes for evaluation of pathogenesis of epithelial ovarian cancer (EOC). Materials and Methods: In this study, we have studied on EOC patients' serum and whole blood, healthy control (HC) serum, and whole blood samples. Sixteen serum samples were collected to compare miRNA expression analysis through microarray. According to microarray results, one of the dysregulated miRNA in serum, hsa-let-7d-3p, was validated by RT-qPCR for discriminate two groups. The hsa-let-7d-3p is one of the tumor suppressive let-7d family members. Let-7d is downregulated in numerous types of cancer, including ovarian cancer and directly targets various oncogenes. We analyzed the let-7d targets, which are High Mobility Group A2 (HMGA2) and (Kirsten Rat Sarcoma Viral Oncogene Homolog), as the oncogenes that are associated with EOC. The relation between target genes of hsa-let-7d-3p and EOC has been examined by Pathway Studio. Twenty serum and whole blood samples collected to analyze expression level of target genes were analyzed by real-time PCR. Results: 31 significantly dysregulated miRNAs were identified by microarray in serum. Hsa-let-7d-3p has been selected for the validation, according to P-value and dysregulated level. RT-qPCR results showed that hsa-let-7d-3p could discriminate EOC patients from HC (P = 0.0484, AUC = 0.7). Furthermore, we identified hsa-let-7d-3p's target genes (HMGA2, KRAS) by bioinformatic analysis. The expression level of genes could discriminate patients with EOC from HC, with a power area under the ROC curves (AUC) of 62 and 64.2, respectively. Conclusion: HMGA2 and KRAS could be translationally downregulated by the hsa-let-7d-3p, and the loss of hsa-let-7d-3p expression led to the progression of EOC related to the tumorigenesis, invasion, and metastasis