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Endometrial carcinoma (EC) is a rising concern among gynecological malignancies. Iroquois Homeobox 2 (IRX2), a member of the Iroquois homeobox gene family, demonstrates variable effects in different cancer types, emphasizing the need for extensive exploration of its involvement in EC progression. Utilizing TCGA and GEO databases, as well as performing immunohistochemistry (IHC) analysis on clinical samples, we assessed the expression levels of IRX2 and its promoter methylation in EC. To understand the functional roles of IRX2, we conducted various assays including in vitro CCK-8 assays, colony formation assays, cell invasion assays, and cell apoptosis assays. Moreover, we utilized in vivo subcutaneous xenograft mouse models. Additionally, we performed KEGG pathway and gene set enrichment analyses to gain insights into the underlying mechanisms. To validate the regulatory relationship between IRX2 and RUVBL1, we employed chromatin immunoprecipitation and luciferase reporter assays. Our results indicate significantly reduced levels of IRX2 expression in EC, correlating with higher histological grades, advanced clinical stages, and diminished overall survival. We observed that DNA methylation of the IRX2 promoter suppresses its expression in EC, with cg26333652 and cg11793269 playing critical roles as methylated sites. In contrast, ectopic overexpression of IRX2 substantially inhibits cell proliferation and invasion, and promotes cell apoptosis. Additionally, we discovered that IRX2 exerts negative regulation on the expression of RUVBL1, which is upregulated in EC and associated with a poorer prognosis. In conclusion, our findings indicate that decreased expression of IRX2 facilitates EC cell growth through the regulation of RUVBL1 expression, thereby contributing to the development of EC. Hence, targeting the IRX2-RUVBL1 axis holds promise as a potential therapeutic strategy for EC treatment.
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Neoplasias Endometriales , MicroARNs , Femenino , Humanos , Animales , Ratones , Transformación Celular Neoplásica/genética , Genes Homeobox , Apoptosis/genética , Neoplasias Endometriales/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proteínas Portadoras/metabolismo , ADN Helicasas/metabolismoRESUMEN
We aimed to identify whether Rho GTPase activating proteins (RhoGAPs) were downregulated in cervical cancers and might be targeted to reduce the growth of cervical cancer using the GEO database and immunohistochemical analysis to identified changes in transcription and protein levels. We analyzed their proliferation, clone formation ability, and their growth as subcutaneous tumors in mice. To detect ARHGAP30 localization in cells, immunofluorescence assays were conducted. Mass spectrometry combined with immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation assays. Western-blot and q-PCR were applied to analyze candidate binding proteins that were associated with ribosome biogenesis. Puromycin incorporation assay was used to detect the global protein synthesis rate. We identified that ARHGAP30 was the only downregulated RhoGAP and was related to the survival of cervical cancer patients. Overexpression of ARHGAP30 in cervical cancer cells inhibited cell proliferation and migration. ARHGAP30 immunoprecipitated proteins were enriched in the ribosome biogenesis process. ARHGAP30 was located in the nucleous and interacted with nucleolin (NCL). Overexpression of ARHGAP30 inhibited rRNA synthesis and global protein synthesis. ARHGAP30 overexpression induced the ubiquitination of NCL and decreased its protein level in Hela cells. The function of ARHGAP30 on cervical cancer cell ribosome biogenesis and proliferation was independent of its RhoGAP activity as assessed with a RhoGAP-deficient plasmid of ARHGAP30R55A . Overall, the findings revealed that ARHGAP30 was frequently downregulated and associated with shorter survival of cervical cancer patients. ARHGAP30 may suppress growth of cervical cancer by reducing ribosome biogenesis and protein synthesis through promoting ubiquitination of NCL.
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Proliferación Celular , Proteínas Activadoras de GTPasa/metabolismo , Ribosomas/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Animales , Línea Celular Tumoral , Nucléolo Celular/metabolismo , Regulación hacia Abajo , Femenino , Células HeLa , Humanos , Inmunoprecipitación , Espectrometría de Masas , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Biosíntesis de Proteínas , ARN Ribosómico/biosíntesis , Proteínas de Unión al ARN/metabolismo , Ensayo de Tumor de Célula Madre , Ubiquitinación , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , NucleolinaRESUMEN
PURPOSE: The dysregulation of long noncoding RNAs (lncRNAs) has been reported to be correlated to carcinogenesis and cancer progression. Endometrial cancer (EC), arising from the endometrium or the inner lining of the uterus, is one of the most common gynecological malignancies. We aim to explore the prognostic value of the lncRNAs in patients with endometrioid endometrial cancer (EEC) and to identify the potential lncRNA signature for predicting survival of patients with EEC. METHODS: We performed a genome-wide analysis of the lncRNA expression profiling in The Cancer Genome Atlas (TCGA)-Uterine Corpus Endometrial Carcinoma database (408 EEC) to identify the prognosis related lncRNAs for the EEC. The patients with EEC were randomly divided into a training set (204 for endometrioid) and a testing set (204 for endometrioid). The lncRNA signature was identified in the training set, and then independently validated in the testing set and the complete set (training set plus testing set). RESULTS: We developed a nine-lncRNA signature-based risk score in the patients with EEC. The risk score based on the novel lncRNAs signature was able to separate patients of training set into high-and low-risk groups with significantly different overall survival and progression-free survival. These can also be successfully confirmed in the testing set and complete set. CONCLUSION: A nine-lncRNA expression signature was identified and validated which can predict EEC patient's survival. These findings may have important implications in the understanding of the potential therapeutic methods for patients with EEC.
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AIM: We sought to explore the mechanisms of cervical carcinoma response to epidermal growth factor (EGF), and then identify biologically active small molecules capable of targeting the sub-pathways that were dysregulated in cervical cancer cells in the response to EGF. MATERIAL AND METHODS: Differentially expressed genes and pathways were analyzed based on the transcription profile of GSE6783, and then the differentially expressed molecules were further analyzed by several bioinformatics methods. RESULTS: Our results suggested that EGF could promote cervical cancer cell proliferation through triggering the dysregulation of certain sub-pathways in the mitogen-activated protein kinase signaling pathway, p53 signaling pathway and pathways in cancer. Furthermore, our bioinformatics analysis revealed a total of 49 small molecules which may play a role in perturbing the response to EGF of cervical cancer cells. CONCLUSIONS: Candidate drugs identified by our approach may provide the groundwork for a combination therapy approach for cervical cancer; however, further studies are still needed to make sure that the use of parthenolide or other anti-cancer agents is effective without inhibiting important host defense mechanisms in cervical cancer.
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Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Factor de Crecimiento Epidérmico/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias del Cuello Uterino/tratamiento farmacológico , Carcinoma/metabolismo , Proliferación Celular , Biología Computacional , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Femenino , Perfilación de la Expresión Génica , Humanos , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/metabolismoRESUMEN
AIM: Endometrial carcinoma (EC) is a common gynecologic malignancy. EC has a favorable prognosis because it is usually diagnosed at an early stage. However, the recurrence rate is high and the prognosis is poor for high-risk EC. Identification of new biomarkers for the prediction of high-risk features will help to guide the treatment and improve the prognosis of patients with EC. MATERIAL AND METHODS: Differentially expressed proteins among high-risk EC, low-risk EC, and normal endometrial tissues were determined by two-dimensional gel electrophoresis (2-DE) and a liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) proteomics approach. Then, the candidate proteins were examined by immunohistochemical analysis. RESULTS: Thirteen protein spots were differentially expressed between the high- and low-risk groups, and 25 protein spots were differentially expressed between the high-risk and normal endometrium groups. Twenty-two proteins were identified by MS analysis. PKM2 and HSPA5 were elevated in the high-risk EC tissues compared with both the low-risk EC and normal endometrial tissues. The elevated expression of PKM2 and HSPA5 in high-risk EC tissue was confirmed by immunohistochemical analysis. DISCUSSION: PKM2 and HSPA5 may play an important role in the progression of EC. These two proteins are potential biomarkers to better predict high-risk EC and thereby guide clinical therapy.
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Biomarcadores de Tumor/metabolismo , Carcinoma Endometrioide/diagnóstico , Proteínas Portadoras/metabolismo , Neoplasias Endometriales/diagnóstico , Proteínas de Choque Térmico/metabolismo , Proteínas de la Membrana/metabolismo , Hormonas Tiroideas/metabolismo , Anciano , Carcinoma Endometrioide/metabolismo , Electroforesis en Gel Bidimensional , Neoplasias Endometriales/metabolismo , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Proteómica/métodos , Espectrometría de Masas en Tándem , Proteínas de Unión a Hormona TiroideRESUMEN
Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel activated by various stimuli, such as heat. A recent study reported that high expression of TRPV4 predicted a poor prognosis in ovarian cancer patients. This study demonstrated that TRPV4 was highly expressed in ovarian cancer and had the ability to promote proliferation and migration. Through RNA-seq and related experiments, we confirmed that the oncogenic pathway of TRPV4 in ovarian cancer may be related to the fatty acid synthesis. By correlation analysis and RNA-seq, we demonstrated that SREBP1 and mTORC1 were inseparably related to that. Therefore, we used inhibitors to perform experiments. Calcium fluorescent probe experiments suggest that the change of calcium content in ovarian cancer cells was related to the downstream mTORC1 signaling pathway and fatty acid synthesis. These results confirmed that TRPV4 affected the fatty acid synthesis through the calcium-mTOR/SREBP1 signaling pathway, thereby promoting ovarian cancer progression.
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OBJECTIVE: To analyze the influence of epidermal growth factor receptor inhibitor AG1478 on the proliferation and epithelial-mesenchymal transition in endometrial carcinoma cells. MATERIALS AND METHODS: The inhibitory effect of different concentrations of AG1478 on the proliferation of endometrial carcinoma cells was detected by tetrazolium-based assay. Western blot was applied to investigate the influence of AG1478 on expressions of epithelium-cadherin, α-catenin, neural cadherin, vimentin, matrix metalloproteinase 9 (MMP9), and MMP2 protein in endometrial carcinoma cells. The influence of AG1478 on migration and invasion of endometrial carcinoma cells was examined by Transwell migration and invasion assay, respectively. RESULTS: AG1478 could suppress the proliferation of different endometrial carcinoma cells, and cells transfected with epidermal growth factor receptor were more sensitive (P < 0.05). The expression of an increase in epithelial marker proteins and a decrease in mesenchymal marker proteins, MMP9, MMP2 were observed in endometrial carcinoma cells after AG1478 treated. This effect was more obvious in cells transfected with epidermal growth factor receptor (P < 0.05). The migration and invasion ability of endometrial carcinoma cells were suppressed by AG1478, and Ishikawa cells transfected with epidermal growth factor receptor were demonstrated to be more sensitive to AG1478 (P < 0.05). CONCLUSIONS: Epidermal growth factor receptor inhibitor AG1478 could effectively inhibit the proliferation and epithelial-mesenchymal transition of endometrial carcinoma cells.
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Carcinoma/patología , Neoplasias Endometriales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Quinazolinas/farmacología , Tirfostinos/farmacología , Carcinoma/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Neoplasias Endometriales/metabolismo , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Células Tumorales CultivadasRESUMEN
AIM: The aim of these investigations was to study the role of gefitinib (a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor) on reversing progestin-resistance in a human endometrial carcinoma xenograft model. MATERIAL AND METHODS: To study the effect of gefitinib and epidermal growth factor receptor (EGFR) overexpression on tumor progestin resistance, the Ishikawa endometrial carcinoma cell line was transfected to stably express a high level of EGFR, which resulted in the progestin-resistant Ishikawa-pLWERNL subcell line. BALB/c nude mice were injected subcutaneously with the parental Ishikawa cell line and the Ishikawa-pLWERNL cell line. Therapy experiments with gefitinib alone or in combination with medroxyprogesterone acetate (MPA) were done and samples were analyzed for EGFR and progesterone receptor isoform B (PR-B) expression by Western blot and immumohistochemistry analyses. Role in blocking EGFR autophosphorylation and its downstream signaling pathway and antagonizing progestin resistance by gefitinib was investigated by Western blot analysis. RESULTS: EGFR expression was higher in progestin-resistant Ishikawa-pLWERNL endometrial cancer (EC) xenografts than in progestin-sensitive Ishikawa EC xenografts; in contrast, PR-B was higher in Ishikawa xenografts than in Ishikawa-pLWERNL xenografts. Higher EGFR expression reduced sensitivity to progestin and decreased PR-B expression in Ishikawa xenografts; it also abnormally activated EGFR autophosphorylation and its downstream signaling pathway. Gefitinib effectively inhibited the proliferation of EC xenografts that overexpressed EGFR, and reversed hormone resistance in progestin-resistant EC xenografts. DISCUSSION: The present study describes an in vivo model that can provide a valuable tool in studying the interaction of overexpressed EGFR and progestin resistance in EC. Gefitinib may be useful in the treatment of progestin-resistant EC.
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Antineoplásicos Hormonales/uso terapéutico , Carcinoma/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Endometriales/tratamiento farmacológico , Receptores ErbB/metabolismo , Acetato de Medroxiprogesterona/uso terapéutico , Quinazolinas/uso terapéutico , Animales , Antineoplásicos Hormonales/farmacología , Carcinoma/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Quimioterapia Combinada , Neoplasias Endometriales/metabolismo , Receptores ErbB/antagonistas & inhibidores , Femenino , Gefitinib , Humanos , Inmunohistoquímica , Acetato de Medroxiprogesterona/farmacología , Ratones , Ratones Endogámicos BALB C , Fosforilación/efectos de los fármacos , Quinazolinas/farmacología , Receptores de Progesterona/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: To retrospectively analyze the relationships of peritoneal serum relative to venous serum (R (p/v)) ratios for human chorionic gonadotropin, CA-125, and creatine kinase to the ectopic pregnancy (EP). METHODS: Intra-abdominal fluid and venous blood samples of 118 subjects with suspected EP were obtained for biomarker measurements. R (p/v-hCG) >1 was considered indicative of EP, and final diagnosis was based on surgical finding of an ectopic chorionic villous or gynecological ultrasound finding of an intrauterine gestational sac. RESULTS: R (p/v-hCG) and R (p/v-CA-125) were both significantly greater for abortive as compared to ruptured EP and for the absence as compared to presence of active bleeding. However, neither ratio differed significantly between ampullary and isthmic EP. R (p/v-hCG) and R (p/v-CA-125) correlated negatively with hemoperitoneum volume. R (p/v-hCG) exhibited only modest predictive value for rupture. However, with R (p/v-CA-125) as the diagnostic criterion for rupture, sensitivity and specificity were 66.7 and 100%, respectively; in patients initially diagnosed with EP, R (p/v-CA-125) values <22.43 effectively predicted rupture. R (p/v-CK) did not exhibit significant diagnostic value. CONCLUSIONS: R (p/v-hCG) values >1 combined with positive culdocentesis test findings reliably indicate the presence of EP. In patients initially diagnosed with EP, R (p/v-CA-125) values <22.43 predict tubal rupture.
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Embarazo Ectópico/sangre , Embarazo Ectópico/diagnóstico , Adulto , Biomarcadores/sangre , Antígeno Ca-125/sangre , Gonadotropina Coriónica/sangre , Vellosidades Coriónicas/diagnóstico por imagen , Vellosidades Coriónicas/cirugía , Creatina Quinasa/sangre , Femenino , Saco Gestacional/diagnóstico por imagen , Saco Gestacional/cirugía , Humanos , Valor Predictivo de las Pruebas , Embarazo , Embarazo Ectópico/diagnóstico por imagen , Curva ROC , Estudios Retrospectivos , Sensibilidad y Especificidad , Ultrasonografía , Rotura Uterina/sangre , Rotura Uterina/diagnóstico , Rotura Uterina/diagnóstico por imagen , Adulto JovenRESUMEN
Ovarian cancer (OC) is the deadliest form of gynecologic malignancy, with the majority of patients being diagnosed only once the disease reaches an advanced stage owing to a lack of available biomarkers capable of accurately detecting the disease. Stable circular RNAs (circRNAs) can be found at high levels in exosomes, and there is evidence to suggest that they may be viable diagnostic biomarkers for certain cancers. However, circRNAs in the serum of OC patients have rarely been evaluated to date. We therefore sought to investigate serum circRNA profiles of OC patients, and to explore whether these sorts of circRNAs could be used to detect early OC, serving as biomarkers of disease that may allow for the earlier treatment thereof. Second-generation sequencing was used to screen differentially expressed circRNAs in OC patient serum and also in the serum obtained from healthy controls, and circRNA expression was confirmed by qPCR. A bioinformatics-based approach was then used to assess what biological functions might be affected be the altered regulation of these RNA molecules. We further conducted GO, KEGG, and network analyses to further explore the expression of circRNAs. We detected 178 differentially expressed circRNAs in OC patient serum, of which 175 were up-regulated and 3 were down-regulated. We validated 5 of these identified circRNAs by qPCR to confirm their expression, and further found these RNAs to be closely linked with FC gamma R-mediated phagocytosis, VEGF signaling, Transcriptional misregulation in cancer, Chemokine signaling, ErbB signaling, and TNF signaling based on conducted analyses. This study provides a profile of circRNAs in OC patient serum, revealing a pattern of dysregulation of these RNAs associated with OC. Our bioinformatics analysis suggested that these circRNAs are likely related to OC development, and as such they may be viable novel OC biomarkers.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/genética , ARN/sangre , Sitios de Unión , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Biología Computacional/métodos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Humanos , ARN/genética , ARN Circular , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignancies among women. Maternal embryonic leucine Zipper Kinase (MELK) is upregulated in a variety of human tumors, where it contributes to malignant phenotype and correlates with a poor prognosis. However, the biological function of MELK in EC progression remains largely unknown. METHODS: We explored the MELK expression in EC using TCGA and GEO databases and verified it using clinical samples by IHC methods. CCK-8 assay, colony formation assay, cell cycle assay, wound healing assay and subcutaneous xenograft mouse model were generated to estimate the functions of MELK and its inhibitor OTSSP167. qRT-PCR, western blotting, co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanism concerning MELK during the progression of EC. FINDINGS: MELK was significantly elevated in patients with EC, and high expression of MELK was associated with serous EC, high histological grade, advanced clinical stage and reduced overall survival and disease-free survival. MELK knockdown decreased the ability of cell proliferation and migration in vitro and subcutaneous tumorigenesis in vivo. In addition, high expression of MELK could be regulated by transcription factor E2F1. Moreover, we found that MELK had a direct interaction with MLST8 and then activated mTORC1 and mTORC2 signaling pathway for EC progression. Furthermore, OTSSP167, an effective inhibitor, could inhibit cell proliferation driven by MELK in vivo and vitro assays. INTERPRETATION: We have explored the crucial role of the E2F1/MELK/mTORC1/2 axis in the progression of EC, which could be served as potential therapeutic targets for treatment of EC. FUNDING: This research was supported by National Natural Science Foundation of China (No:81672565), the Natural Science Foundation of Shanghai (Grant NO:17ZR1421400 to Dr. Zhihong Ai) and the fundamental research funds for central universities (No: 22120180595).
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Progresión de la Enfermedad , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Estudios de Cohortes , Factor de Transcripción E2F1/metabolismo , Neoplasias Endometriales/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Modelos Biológicos , Análisis Multivariante , Naftiridinas/farmacología , Pronóstico , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genética , Homóloga LST8 de la Proteína Asociada al mTOR/metabolismoRESUMEN
BACKGROUND: In China, secondary cytoreductive surgery (SCR) has been widely used in ovarian cancer (OC) over the past two decades. Although Gynecologic Oncology Group-0213 trial did not show its overall survival benefit in first relapsed patients, the questions on patient selection and effect of subsequent targeting therapy are still open. The preliminary data from our pre-SOC1 phase II study showed that selected patients with second relapse who never received SCR at recurrence may still benefit from surgery. Moreover, poly(ADP-ribose) polymerase inhibitors (PARPi) maintenance now has been a standard care for platinum sensitive relapsed OC. To our knowledge, no published or ongoing trial is trying to answer the question if patient can benefit from a potentially complete resection combined with PARPi maintenance in OC patients with secondary recurrence. METHODS: SOC-3 is a multi-center, open, randomized, controlled, phase II trial of SCR followed by chemotherapy and niraparib maintenance vs chemotherapy and niraparib maintenance in patients with platinum-sensitive second relapsed OC who never received SCR at recurrence. To guarantee surgical quality, if the sites had no experience of participating in any OC-related surgical trials, the number of recurrent lesions evaluated by central-reviewed positron emission tomography-computed tomography image shouldn't be more than 3. Eligible patients are randomly assigned in a 1:1 ratio to receive either SCR followed by 6 cycles of platinum-based chemotherapy and niraparib maintenance or 6 cycles of platinum-based chemotherapy and niraparib maintenance alone. Patients who undergo at least 4 cycles of chemotherapy and must be, in the opinion of the investigator, without disease progression, will be assigned niraparib maintenance. Major inclusion criteria are secondary relapsed OC with a platinum-free interval of no less than 6 months and a possibly complete resection. Major exclusion criteria are borderline tumors and non-epithelial ovarian malignancies, received debulking surgery at recurrence and impossible to complete resection. The sample size is 96 patients. Primary endpoint is 12-month non-progression rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03983226.
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Procedimientos Quirúrgicos de Citorreducción , Indazoles/uso terapéutico , Neoplasias Ováricas , Piperidinas/uso terapéutico , Adolescente , China , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Tomografía Computarizada por Tomografía de Emisión de Positrones , Calidad de VidaRESUMEN
Up to 30% of failure rate in endometrial hyperplasia patients treated by progestin urges more detailed understanding of the mechanisms involved in progestin resistance. Survivin is a key regulator in the antiapoptotic network, and overexpression of survivin has been reported in endometrial hyperplasia and cancer. This study investigated the role of survivin in progestin resistance in endometrial hyperplasia. Pre- and post-treatment endometrial hyperplasia tissue samples from 23 women were examined for changes in survivin expression related to the administration of progestins. The impact of continuous or intermittent progestin treatment on survivin expression in Ishikawa cells was examined by the western blot. Survivin immunoreactivity was present in epithelial compartment of all pre-progestin-treated endometrial hyperplasia samples with mean nuclear indices 78 and cytoplasmic indices 114. In the 15 progestin responders, an average of 19.5-fold decrease of survivin expression was seen in epithelial nuclei (P<0.001) and 8-fold decrease in epithelial cytoplasm (P<0.001). In the eight non-responders, no significant changes in survivin expression were detected. With in vitro Ishikawa cells, survivin expression was effectively inhibited by either 72-h continuous treatment with 10 muM medroxyprogesterone acetate or 72 h after medroxyprogesterone acetate withdrawal. Our results indicated that dysregulation of survivin expression in hyperplastic endometrium may be part of the molecular mechanisms for progestin resistance. Intermittent, rather than continuous, progestin treatment may be more effective clinically for the treatment of endometrial hyperplasia.
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Resistencia a Medicamentos/genética , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/metabolismo , Proteínas Asociadas a Microtúbulos/biosíntesis , Progestinas/administración & dosificación , Adulto , Biomarcadores/análisis , Western Blotting , Hiperplasia Endometrial/genética , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Proteínas Inhibidoras de la Apoptosis , Proteínas Asociadas a Microtúbulos/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , SurvivinRESUMEN
OBJECTIVE: To evaluate the accuracy, sensitivity, and specificity of DNA quantitative cytology test for the diagnosis of endometrial cancer or precancerous lesions and then discuss the value of DNA quantitative cytology as a screening tool for endometrial cancer. METHODS: The study enrolled 575 patients from September 2013 to January 2017 in Shanghai Minhang Central Hospital. Endometrial hysteroscopy plus dilation and curettage and DNA quantitative cytology tests were conducted as a method for the diagnosis of endometrial cancer. The accuracy, sensitivity, and specificity of this method were calculated according to histopathologic diagnoses which were used as the gold standard for diagnosis confirmation. RESULTS: For the DNA quantitative cytology diagnosis of endometrial cancer, accuracy was estimated at 85.57%, sensitivity at 87.01%, specificity at 85.34%, positive predictive value (PPV) at 47.86%, and negative predictive value (NPV) at 97.07%. For the DNA quantitative cytology diagnosis of endometrial cancer in menopausal patients: accuracy was estimated at 89.95%, sensitivity at 97.73%, specificity at 87.59%, positive predictive value (PPV) at 70.49%, negative predictive value (NPV) at 99.22%. For the DNA quantitative cytology diagnosis of endometrial cancer in non-menopausal patients, accuracy was estimated at 83.42%, sensitivity at 72.73%, specificity at 84.42%, positive predictive value (PPV) at 30.38%, and negative predictive value (NPV) at 97.07%. CONCLUSION: DNA heteroploidy can be tested for the occurrence and the development of endometrial cancer. A small number of non-endometrial cancer cases may also appear DNA heteroploidy, but the number of >5c cells is less than 3. DNA quantitative analysis is a useful tool for the screening of endometrial cancer, worthy of being popularized and applied in endometrial cancer diagnosis.
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Endometrial carcinoma is the most common gynecological malignancy of the female genital tract worldwide (2012). Enhancer of zeste homolog 2 (EZH2), a critical component of the polycomb repressive complex 2, has been found to be associated with multiple biological processes and is overexpressed in multiple types of cancer. Previous studies have demonstrated that EZH2 is associated with endometrial carcinoma. The present study investigated the expression and biology function of EZH2 in endometrial cancer (EC). It was found that EZH2 levels were markedly increased in endometrial cancer tissues compared with that in adjacent normal tissues. EZH2 was significantly overexpressed in 3 separate endometrial cancer cell lines (Ishikawa, RL95-2 and HEC1-A) when compared with the normal endometrial cell line ESC. Additionally, small interfering RNA was used to investigate the role of EZH2 in endometrial carcinoma cell proliferation, and the results showed that EZH2 knockdown suppressed the proliferation of endometrial carcinoma cells in vitro. Furthermore, EZH2 knockdown induced apoptosis of human EC cells by promoting the expression of pro-apoptosis protein caspase 3, caspase 9, BCL2 associated X and decreasing the expression of anti-apoptosis protein Bcl-2. Finally, the present study demonstrated that EZH2 knockdown suppressed the invasion of EC cells through downregulation of the epithelial-mesenchymal transition. Collectively, these data demonstrate that EZH2 is frequently overexpressed in EC cells and its overexpression is associated with promoting the proliferation and invasion and decreasing the apoptosis of EC cells, suggesting that EZH2 may provide potential therapeutic targets for treatment of endometrial carcinoma.
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High-risk human papillomavirus oncoproteins E6 and E7 are the major etiological factors of cervical cancer but are insufficient for malignant transformation of cervical cancer. Dysregulated alternative splicing, mainly ascribed to aberrant splicing factor levels and activities, contributes to most cancer hallmarks. However, do E6 and E7 regulate the expression of splicing factors? Does alternative splicing acts as an "accomplice" of E6E7 to promote cervical cancer progression? Here, we identified that the splicing factor SRSF10, which promotes tumorigenesis of cervix, was upregulated by E6E7 via E2F1 transcriptional activation. SRSF10 modulates the alternate terminator of interleukin-1 receptor accessory protein exon 13 to increase production of the membrane form of interleukin-1 receptor accessory protein. SRSF10-mediated mIL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis by promoting nuclear factor-κB activation, which is pivotal in inflammatory, immune, and tumorigenesis processes. Altogether, these data reveal a close relationship among HPV infection, alternative splicing and tumor immune evasion, and also suggests that the SRSF10-mIL1RAP-CD47 axis could be an attractive therapeutic target for the treatment of cervical cancer.
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Empalme Alternativo/genética , Carcinogénesis/genética , Proteínas de Ciclo Celular/fisiología , Proteína Accesoria del Receptor de Interleucina-1/genética , Proteínas Represoras/fisiología , Factores de Empalme Serina-Arginina/fisiología , Neoplasias del Cuello Uterino/genética , Animales , Antígeno CD47/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Transformación Celular Viral/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Papillomavirus Humano 16/fisiología , Papillomavirus Humano 18/fisiología , Humanos , Ratones , Ratones Desnudos , FN-kappa B/metabolismo , Isoformas de Proteínas/genética , Transducción de Señal/genética , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virologíaRESUMEN
OBJECTIVES: Ectopic pregnancies are among the leading causes of maternal morbidity and mortality in both developed and emerging nations, but tests for early, accurate, and convenient detection are lacking. STUDY DESIGN: Between January 2013 and February 2015, 504 women with tubal pregnancy were prospectively recruited, and their clinical characteristics were recorded. Samples of peritoneal fluid were collected by culdocentesis, and venous blood was drawn from the antecubital vein. In samples from each source, levels of the following biochemical markers were measured: cancer antigen 125 (CA125), human chorionic gonadotropin (hCG), progesterone, vascular endothelial growth factor, and creatine kinase. RESULTS: The ratios of biochemical markers in the peritoneal fluid and in the blood (Rp/v) were calculated. The median of Rp/v-CA125 and Rp/v-hCG were significantly lower in the ruptured ectopic pregnancy group than in the unruptured group. The optimal cutoff value to detect ectopic pregnancy rupture was 401.5U/mL as the upper limit for peritoneal CA125, with a sensitivity of 93.5% and specificity of 74.2%. The optimal cutoff value was 18.7 as the upper limit in the peritoneal fluid/blood ratio (Rp/v) of CA125, with a sensitivity of 77.5% and specificity of 68.4%. CONCLUSIONS: In countries with poor access to laparoscopy, culdocentesis is useful. In this study, culdocentesis provided additional information for management of abdominal pain when laparoscopy is not available. The authors propose Rp/v cutoff values that can be used conveniently and quickly to diagnose ruptured ectopic pregnancies and bleeding, enabling rapid and appropriate therapeutic responses.
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Líquido Ascítico/química , Biomarcadores/sangre , Embarazo Tubario/sangre , Adulto , Antígeno Ca-125/sangre , Gonadotropina Coriónica/sangre , Creatina Quinasa/sangre , Femenino , Humanos , Proteínas de la Membrana/sangre , Paracentesis , Embarazo , Embarazo Tubario/diagnóstico , Progesterona/sangre , Estudios Prospectivos , Rotura Espontánea/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto JovenRESUMEN
3ß-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.
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Neoplasias Endometriales/enzimología , Neoplasias Endometriales/patología , Endometrio/anomalías , Insulina/efectos adversos , Proteínas del Tejido Nervioso/biosíntesis , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/biosíntesis , Regulación hacia Arriba/genética , Enfermedades Uterinas/enzimología , Anciano , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Endometrio/enzimología , Endometrio/patología , Inducción Enzimática/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Acetato de Medroxiprogesterona/farmacología , Acetato de Medroxiprogesterona/uso terapéutico , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Pronóstico , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Factor de Transcripción STAT3/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Enfermedades Uterinas/genética , Enfermedades Uterinas/patologíaRESUMEN
Cisplatin is currently one of the most effective chemotherapeutic drugs used for treating ovarian cancer; however, resistance to cisplatin is common. In this study, we explored an experimental strategy for overcoming cisplatin resistance of human ovarian cancer from the new perspective of cancer cell metabolism. By using two pairs of genetically matched cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines, we tested the hypothesis that downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable α subunit of HIF-1, HIF-1α, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1α degradation but did not downregulate HIF-1α in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1α (HIF-1α ΔODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1α or pharmacological promotion of HIF-1α degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. We further demonstrated that knockdown of HIF-1α improved the response of cisplatin-resistant ovarian cancer cells to cisplatin by redirecting the aerobic glycolysis in the resistant cancer cells toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of reactive oxygen species. Our findings suggest that the HIF-1α-regulated cancer metabolism pathway could be a novel target for overcoming cisplatin resistance in ovarian cancer.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Resistencia a Antineoplásicos , Glucólisis/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Fosforilación Oxidativa/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Lactato Deshidrogenasa 5 , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Estrés Oxidativo/efectos de los fármacos , Proteolisis , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , TransfecciónRESUMEN
Nanostructured CoNi2 S4 materials with different morphologies were successfully grown on carbon cloth through a facile precursor transformation method by adjusting the anions in nickel cobalt salts. The resulting samples were characterized by XRD, EDS, FESEM, and TEM and were found to display different morphologies. Their electrochemical performance was investigated by means of cyclic voltammetry (CV), galvanostatic charge-discharge, electrochemical impedance spectroscopy (EIS), and cycle life. The as-obtained CoNi2 S4 sample with NO3 - as the anion in the nickel cobalt salt displayed an ultrahigh specific capacitance of 2714â F g-1 at 1â A g-1 and excellent rate capability (64.8 % capacity retention at 20â A g-1 ). However, the as-obtained CoNi2 S4 samples with SO4 2- and Cl- as the anions in the precursors displayed a limited specific capacitance of only 1750 and 1334â F g-1 , respectively. Besides, they also displayed different performances in the cycle life test. The study indicates that the as-obtained CoNi2 S4 grown on carbon cloth prepared with NO3 - as the anion will be a promising electrode material for supercapacitors.