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Introduction: Ovarian cancer remains to be a significant cause of global cancer-related mortality. In recent years, there has been a surge of studies in investigating the application of nanomaterials in the diagnosis and treatment of ovarian cancer. This study aims to conduct a comprehensive bibliometric analysis regarding nanomaterial-based researches on ovarian cancer to evaluate the current state and emerging patterns in this field. Methods: A thorough literature search on the Web of Science Core Collection database was conducted to identify articles focused on nanomaterial-based ovarian cancer researches. The studies that met the inclusion criteria were selected for further analysis. VOSviewer and CiteSpace were applied for the bibliometric and visual analyses of the selected publications. Results: A total of 2,426 studies were included in this study. The number of annual publications showed a consistent upward trend from 2003 to 2023. Notably, China, the United States, and India have emerged as the leading contributors in this field, accounting for 37.39%, 34.04%, and 5.69% of the publications, respectively. The Chinese Academy of Sciences and Anil K. Sood were identified as the most influential institution and author, respectively. Furthermore, the International Journal of Nanomedicine was the most frequently cited journal. In terms of the research focus, significant attention has been directed towards nanomaterial-related drug delivery, while the exploration of immunogenic cell death and metal-organic frameworks represented recent areas of interest. Conclusion: Through comprehensive analyses, an overview of current research trends and emerging areas of interest regarding the application of nanomaterials in ovarian cancer was illustrated. These findings offered valuable insights into the status and future directions of this dynamic field.
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Endometrial cancer (EC), the second most common malignancy in the female reproductive system, has garnered increasing attention for its genomic heterogeneity, but understanding of its metabolic characteristics is still poor. We explored metabolic dysfunctions in EC through a comprehensive multi-omics analysis (RNA-seq datasets from The Cancer Genome Atlas [TCGA], Cancer Cell Line Encyclopedia [CCLE], and GEO datasets; the Clinical Proteomic Tumor Analysis Consortium [CPTAC] proteomics; CCLE metabolomics) to develop useful molecular targets for precision therapy. Unsupervised consensus clustering was performed to categorize EC patients into three metabolism-pathway-based subgroups (MPSs). These MPS subgroups had distinct clinical prognoses, transcriptomic and genomic alterations, immune microenvironment landscape, and unique patterns of chemotherapy sensitivity. Moreover, the MPS2 subgroup had a better response to immunotherapy. Finally, three machine learning algorithms (LASSO, random forest, and stepwise multivariate Cox regression) were used for developing a prognostic metagene signature based on metabolic molecules. Thus, a 13-hub gene-based classifier was constructed to predict patients' MPS subtypes, offering a more accessible and practical approach. This metabolism-based classification system can enhance prognostic predictions and guide clinical strategies for immunotherapy and metabolism-targeted therapy in EC.
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Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC ( P <0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immune-related prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve >0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy ( P <0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.
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Neoplasias Endometriales , Linfocitos T Reguladores , Humanos , Femenino , Microambiente Tumoral/genética , Recurrencia Local de Neoplasia , Pronóstico , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/terapia , Linfocitos T CD8-positivosRESUMEN
AIM: The aim of this study was to identify the biological characteristics and potential roles of endometrial progenitor cells in the pathogenesis of endometriosis. BACKGROUND: It is generally believed that progenitor cells in human endometrium are responsible for rapid endometrial regeneration. However, the biological characteristics and potential roles of the paired eutopic and ectopic endometrial progenitor cells in endometriosis remain unclear. OBJECTIVE: This study intends to isolate the epithelial progenitor (EP) cells and endometrial mesenchymal stem cells (eMSCs) from the eutopic and ectopic endometria from endometriosis patients, further to reveal their features and functions respectively. METHODS: The distributions of EP cells and eMSCs and the expression of steroid hormone receptors in the endometrium and endometriotic tissues were assessed by immunohistochemistry. EP cells and eMSCs were sorted from paired eutopic and ectopic endometria with epithelial cell adhesion molecule (EpCAM) magnetic beads. The clonogenicity, cell viability after being treated with estradiol and progesterone, and cell markers expression were evaluated with colony forming on Matrigel, CCK-8 and immunofluorescence staining, respectively. The differentially expressed genes (DEGs) were further identified with RNA sequencing. RESULTS: SSEA-1- and PDGFRß-positive cells were distributed in the epithelial and stromal layers. The ERß staining was much more intense in endometriotic tissues, but PR expression was almost absent. The ectopic EP cells exhibit strong clonogenicity and ERß expression but weak PR expression, leading to progesterone resistance. There are 12604 and 13242 DEGs revealed by RNA sequencing between eutopic and ectopic EP cells or eMSCs. GO and KEGG analyses revealed that the functions and pathways of DEGs enriched in cellular energy metabolism and regulation of the immune response, respectively. Additionally, ERß targets were mainly enriched in ectopic EP cells. CONCLUSION: Both EP cells and eMSCs may engage in ectopic lesion formation in endometriosis by modifying the metabolic mode and immune tolerance. These data not only help to understand the molecular mechanism of endometriosis but also could potentially contribute to the discovery of therapeutic targets for endometriosis.
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Endometriosis , Enfermedades Uterinas , Femenino , Humanos , Endometriosis/etiología , Endometriosis/metabolismo , Endometriosis/patología , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/análisis , Receptor beta de Estrógeno/metabolismo , Endometrio , Enfermedades Uterinas/complicaciones , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patología , Células Madre/metabolismoRESUMEN
OBJECTIVE: To present a novel totally enclosed protective device for tumor isolation in laparoscopic ovarian cystectomy. METHODS: A retrospective study was conducted of 16 patients with unilateral ovarian teratoma in the Department of Obstetrics and Gynecology of the China-Japan Friendship Hospital. Laparoscopic surgery was performed with a totally enclosed protective device for tumor isolation, followed by a case series retrospective study. The indexes measured included size of cyst, rate of intraoperative rupture, duration of operation, amount of intraoperative blood loss, and postoperative length of stay in the hospital. An intact cyst resected in the device with no spillage seen indicated a successful surgery. RESULTS: A total of 16 operations were performed successfully. The mean diameter of the cysts was 7.2 ± 1.4 cm. Of them, 12 (75%) had an intraoperative cyst rupture without spillage. The mean duration of surgery was 1.3 ± 0.1 h and the mean amount of intraoperative blood loss was 12.5 ± 3.2 ml. All postoperative histology tests showed benign cysts. The mean length of stay after surgery was 2.4 ± 0.5 days. No peritonitis-related symptoms or complaints were reported. CONCLUSION: Laparoscopically assisted ovarian cystectomy with a totally enclosed protective device for tumor isolation was confirmed safe and feasible.
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Quistes , Laparoscopía , Quistes Ováricos , Neoplasias Ováricas , Femenino , Embarazo , Humanos , Estudios Retrospectivos , Quistes Ováricos/cirugía , Quistes Ováricos/patología , Pérdida de Sangre Quirúrgica/prevención & control , Cistectomía , Neoplasias Ováricas/cirugía , Quistes/cirugía , Equipos de SeguridadRESUMEN
The existence of Lactobacillus-led colonized bacteria in the endometrium of a healthy human has been reported in recent studies. Unlike the composition of the microbiome in the lower genital tract, that in the endometrium is different and closely associated with the physiological and pathological processes of gynecological diseases. For example, changing the immune microenvironment affects the receptivity of the endometrium, thereby leading to abnormal reproductive outcomes, such as embryo implantation failure and recurrent spontaneous abortion. However, the concrete functions and mechanisms of the endometrial microbiome have not been studied thoroughly. This review elaborates the research progress on the mechanisms by which the endometrial microbiome affects endometrial receptivity from the perspective of endometrial immune microenvironment regulation. Considering the lack of a unified evaluation method for the endometrial microbiome, as well as the lack of an optimal treatment protocol against recurrent spontaneous abortion, we also discussed the application of combining antibiotics with probiotics/prebiotics as precautionary measures.
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Aborto Espontáneo , Microbiota , Antibacterianos/farmacología , Implantación del Embrión/fisiología , Endometrio/microbiología , Femenino , Humanos , EmbarazoRESUMEN
OBJECTIVE: To report a novel multi-port containment (NMC) system for laparoscopic power morcellation to prevent tumoral spread and to evaluate its safety, validity, and feasibility. METHODS: This retrospective study included women who underwent laparoscopic myomectomy (LM) between January 2014 and August 2020 at a single academic institution. The NMC system was used in the study group (n = 193); the control group underwent unprotected LM (n = 1753). RESULTS: After 1:1 propensity score matching, no significant differences in the baseline characteristics were observed between 193 matched pairs. Bag damages were detected in two cases in the study group before morcellation, and the NMC systems were replaced. There were no significant differences between the two groups in terms of the complications, total operative time, estimated blood loss, or postoperative hospitalization duration. In the study group, all operations were completed and no system rupture or leakage was observed. The median follow-up times were 21 and 54 months in the study and control groups, respectively. There was no peritoneal tissue spread in the study group. However, three (3/5, 0.6%) and six (6/1,753, 0.3%) patients in the control group experienced malignant and benign peritoneal tissue spread, respectively. CONCLUSION: The NMC system for laparoscopic power morcellation is valid, safe, and feasible for preventing a tumor spread.
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Piwil2 reprograms HPV-infected reserve cells in the cervix into tumor-initiated cells (TICs) and upregulates Wnt3a expression sequentially, which leads to cervical intraepithelial neoplasia (CIN) and ultimately squamous cell carcinoma (SCC). However, little is known regarding Wnt signaling in the maintenance of TIC stemness during the progression of cervical lesions. We herein investigated the expression of canonical Wnt3a signaling and related genes by microarray data set analysis and immunohistochemical (IHC) staining of samples obtained by biopsy of normal cervix, low- and high-grade CIN, and invasive SCC tissue. Array data analyzed by GEO2R showed higher expression levels of Wnt signaling and their target genes, significant upregulation of stemness-associated markers, and notably downregulated cell differentiation markers in CIN and SCC tissues compared with those in the normal cervix tissue. Further, Gene Set Enrichment Analysis (GSEA) revealed that Wnt pathway-related genes significantly enriched in SCC. IHC staining showed gradually increased immunoreactivity score of Wnt3a and CBP and notable translocation of ß-catenin from the membrane to the cytoplasm and nucleus during the lesion progression. The intensity and proportion of P16, Ki67 and CK17 staining also increased with the progression of cervical lesions, whereas minimal to negative Involucrin expression was observed in CIN2/3 and SCC. Therefore, canonical Wnt signaling may contribute to the progression of CIN to SCC and may be a potential therapeutic target.
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Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Vía de Señalización Wnt/fisiología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Progresión de la Enfermedad , Femenino , Humanos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fragmentos de Péptidos/metabolismo , Sialoglicoproteínas/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Proteína Wnt3A/metabolismo , Displasia del Cuello del Útero/metabolismoRESUMEN
B cell receptor associated protein 31 (BAP31) is a member of the B cell receptor that functions as a transporter for numerous types of newly formed proteins from the endoplasmic reticulum to the Golgi apparatus. Previous studies found that that BAP31 serves an important role in the pathogenesis of malignancy but its specific effect on ovarian cancer is not clear. The present study aimed to investigate whether BAP31 affects ovarian cancer and its underlying mechanism. In the present study, ovarian cancer tissue, human ovarian normal epithelial cell line IOSE80 and five ovarian cancer cell lines (A2780, Hey-T30, COC1, SKOV3 and OVCAR3) underwent reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8, Transwell and co-immunoprecipitation (Co-IP) assay and transcriptome sequencing. Previous studies showed that compared with healthy tissues, the expression level of BAP31 protein was found to be significantly higher in various types of cancer tissues, implying that BAP31 may serve an important role in the pathogenesis of cancer. The present study found that BAP31 expression was upregulated in five ovarian cancer cell lines and ovarian cancer tissue, such that BAP31 knockdown [performed using two short hairpin (sh)RNA plasmids] decreased proliferation, invasion and migration. In addition, BAP31 knockdown was found to downregulate the expression of N-cadherin and upregulate the expression of E-cadherin on transcriptional level by controlling the nuclear aggregation of TWIST1, a transcriptional regulator of N-cadherin and E-cadherin. There was no interaction between BAP31 and E-cadherin or N-cadherin using Co-IP detection, while BAP31, E-cadherin and N-cadherin interacted with TWIST1 protein. E-cadherin and N-cadherin expression levels recovered when TWIST1 was overexpressed in the shBCAP31 cells. These results suggest that BAP31 can regulate the migration and invasion of ovarian cancer cells through the epithelial-mesenchymal transition pathway at the transcriptional level, which may be beneficial for the identification of potentially novel targets for ovarian cancer therapy.
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Our previous work demonstrated that Piwil2 reactivated by the human papillomavirus oncoproteins E6 and E7 may reprogram somatic cells into tumor-initiating cells (TICs), which contribute to cervical neoplasia lesions. Maintaining the stemness of TICs is critical for the progression of cervical lesions. Here, we determined that canonical Wnt signaling was aberrantly activated in HaCaT cells transfected with lentivirus expressing Piwil2 and in cervical lesion specimens of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and invasive carcinoma. Blocking the ß-catenin and CREB binding protein interaction with ICG-001 significantly downregulated the reprogramming factors c-Myc, Nanog, Oct4, Sox2, and Klf4, thus leading to cell differentiation and preventing tumorigenicity in Piwil2-overexpressing HaCaT cells. Similarly, Piwil2 also critically regulated the canonical Wnt signaling pathway in cervical cancer. We further demonstrated that ICG-001 increased cisplatin sensitivity and significantly suppressed tumor growth of cervical cancer alone or in combination with cisplatin both in vitro and in vivo. The ß-catenin/ CREB binding protein-mediated transcription activated by Piwil2 is essential for the maintenance of TICs, therefore contributing to the progression of cervical oncogenesis.
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Proteínas Argonautas/genética , Proteína de Unión a CREB/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/metabolismo , Vía de Señalización Wnt , Animales , Antineoplásicos/farmacología , Proteínas Argonautas/metabolismo , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunohistoquímica , Factor 4 Similar a Kruppel , Ratones , Modelos Biológicos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Vía de Señalización Wnt/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Drug-resistance and metastasis are major reasons for the high mortality of ovarian cancer (OC) patients. Cyclooxygenase-2 (COX-2) plays a critical role in OC development. This study was designed to evaluate the effects of COX-2 on migration and cisplatin (cis-dichloro diammine platinum, CDDP) resistance of OC cells and explore its related mechanisms. METHODS: Cell counting kit-8 (CCK-8) assay was used to detect the cytotoxicity effects of celecoxib (CXB) and CDDP on SKOV3 and ES2 cells. The effect of COX-2 on migration was evaluated via the healing test. Western blot and real-time quantitative polymerase chain reaction (qPCR) were used to analyze E-cadherin, vimentin, Snail, and Slug levels. RESULTS: COX-2 promoted drug-resistance and cell migration. CXB inhibited these effects. The combination of CDDP and CXB increased tumor cell sensitivity, reduced the amount of CDDP required, and shortened treatment administration time. COX-2 upregulation increased the expression of Snail and Slug, resulting in E-cadherin expression downregulation and vimentin upregulation. CONCLUSIONS: COX-2 promotes cancer cell migration and CDDP resistance and may serve as a potential target for curing OC.
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Cisplatino/farmacología , Ciclooxigenasa 2/fisiología , Transición Epitelial-Mesenquimal , Neoplasias Ováricas/patología , Celecoxib/farmacología , Línea Celular Tumoral , Movimiento Celular , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Reacción en Cadena de la PolimerasaRESUMEN
Background: Microcystic stromal tumor is a recently described subtype of ovarian tumor characterized by microcystic pattern and diffuse immunoreactivity for CD10, vimentin, and ß-catenin and negative for EMA. However, its diagnostic criterion and standard treatment remain unclear. Case presentation: We report a rare case of a left side microcystic stromal tumor with diameter about 7 cm in a 25-year-old female and summarize all cases of MCST reported in this study. The present patient underwent left ovarian tumor resection. Generally, the tumor was solid and cystic mixed. Immunohistochemically, the tumor was expressed CD10, WT1, cyclin D1 and vimentin, and nuclear immunoreactivity for ß-catenin but negative for α-inhibin, calretinin, CK AE1/AE3, PLAP, SALL-4, CK7, P53, EMA, CD99, AFP, desmin, CgA, E-cadherin, and melanA. Conclusion: Unilateral ovary, solid-cystic, and a larger than 4-8 cm pelvic mass without serious abdominal pain are its clinical features. The immunophenotype of vimentin+/CD10+/WT-1+/ß-catenin+(nuclei)/cyclin D1+ is supportive of diagnosis. For these patients, unilateral oophorectomy dissection could be selected.
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The molecular basis underlying the aggressive nature and excessive proliferation of cervical squamous cancer cell remains unclear. ΔNp63α is the predominant isotype of p63 expressed in the epithelia and regulates epithelial cell differentiation. The pro-/anti-tumor role of ΔNp63α in different kinds of solid tumors remains controversial and the precise molecular mechanisms are still elusive. In this study, we uncovered the molecular functions of ΔNp63α in cervical squamous cell carcinoma to clarify its roles as a tumor suppressor. We demonstrated that ΔNp63α suppressed cell migration, invasiveness, and tumor growth in SiHa and ME-180 cells with both in vivo and in vitro assays. Mechanistic investigation via RNA-sequencing and chromatin immunoprecipitation-sequencing revealed that ΔNp63α exerted its antitumor capacity via regulating the expression of a cohort of cell junction genes. Further, we showed that ZNF385B and CLDN1 were two direct ΔNp63α targets with significant relevance to cervical squamous cell carcinoma examined in cell cultures, tumor xenografts, and clinic tumors. We also demonstrated that ΔNp63α downregulated NFATC1 to reduce cisplatin resistance. These findings shed new lights on functions of ΔNp63α in tumors and providing novel insights in targeted therapy of cervical cancers.
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Carcinoma de Células Escamosas/prevención & control , Movimiento Celular , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Neoplasias del Cuello Uterino/prevención & control , Animales , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Claudina-1/genética , Claudina-1/metabolismo , Bases de Datos Genéticas , Femenino , Humanos , Ratones , Ratones Desnudos , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Tasa de Supervivencia , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ovarian cancer is the leading cause of death among gynecological malignancies. Cyclooxygenase 2 is widely expressed in various cancer cells and participates in the occurrence and development of tumors by regulating a variety of downstream signaling pathways. However, the function and molecular mechanisms of cyclooxygenase 2 remain unclear in ovarian cancer. Here, we demonstrated that cyclooxygenase 2 was highly expressed in ovarian cancer and the expression level was highly correlated with ovarian tumor grades. Further, ovarian cancer cells with high expression of cyclooxygenase 2 exhibit enhanced proliferation and invasion abilities. Specifically, cyclooxygenase 2 promoted the release of prostaglandin E2 upregulated the phosphorylation levels of phospho-nuclear factor-kappa B p65. Celecoxib, AH6809, and BAY11-7082 all can inhibit the promoting effect of cyclooxygenase 2 on SKOV3 and OVCAR3 cell proliferation and invasion. Besides, celecoxib inhibited SKOV3 cell growth in the xenograft tumor model. These data suggest that high expression of cyclooxygenase 2 promotes the proliferation and invasion of ovarian cancer cells through the prostaglandin E2/nuclear factor-kappa B signaling pathway. Cyclooxygenase 2 may be a potential therapeutic target for the treatment of ovarian cancer.
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Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , FN-kappa B/metabolismo , Neoplasias Ováricas/metabolismo , Animales , Antineoplásicos/farmacología , Celecoxib/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Dinoprostona/antagonistas & inhibidores , Femenino , Humanos , Ratones Desnudos , Clasificación del Tumor , Invasividad Neoplásica/genética , Nitrilos/farmacología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosforilación , Subtipo EP2 de Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sulfonas/farmacología , Trasplante Heterólogo , Xantonas/farmacologíaRESUMEN
The ovary can be infected by a variety of viruses, which may come from the female reproductive tract or the peritoneum. The innate immune responses to viral infection in the human ovary are poorly understood. The present study demonstrated that human ovarian granulosa cells had innate immune activity in response to viral RNA challenge through Toll-like receptor 3 (TLR3) activation. TLR3 was constitutively expressed in the human ovary and predominantly located in granulosa cells of developmental follicles at all stages. Polyinosinic-polycytidylic acid [poly (I:C)], a synthetic viral double-stranded RNA analog, induced innate immune responses in human ovarian granulosa cells and affected endocrine function. Poly (I:C) significantly upregulated proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1ß and type I interferon (IFN-α/ß), and the innate immune responses were significantly reduced by blocking TLR3 signaling. Furthermore, poly (I:C) induced antiviral genes expression, including 2'-5'-oligoadenylate synthetase, Mx GTPase 1, IFN-stimulating gene 15 and double-stranded RNA-activated protein kinase R. In contrast, the expression of P450 aromatase and inhibin was dramatically inhibited by poly (I:C). Both silencing of TLR3 and neutralizing TNF-α reversed the inhibitory effect of poly (I:C) on P450 aromatase and inhibin expression. Our study demonstrates that granulosa cells play a potential role in innate immune protection against viral infection in the normal human ovary, and the innate immune response perturbs cell endocrine function.
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Células de la Granulosa/inmunología , Inmunidad Innata/efectos de los fármacos , Poli I-C/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 3/metabolismo , Adulto , Aromatasa/metabolismo , Células Cultivadas , Femenino , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Humanos , Inhibinas/metabolismo , Cultivo Primario de Células , ARN Bicatenario/inmunología , ARN Viral/inmunología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 3/inmunología , Virosis/inmunología , Virosis/virologíaRESUMEN
It is generally accepted that ovarian cancer is associated with local elevation of gonadotropins (FSH and LH), with repeated ovulation and accompanying expression of inducible cyclooxygenase 2 (COX2). However, the roles of gonadotropins and the concomitant elevation of COX2 in the development of ovarian cancer have not been fully characterized. Herein, we report that excessive FSH/LH exposure did not induce proliferation in ovarian cancer cell lines but significantly promoted cell migration and invasion. Moreover, FSH/LH treatment rapidly upregulated COX2 expression within 24 h, whereas COX1 expression remained unchanged. Further results showed that enhancement of epithelial-mesenchymal transition (EMT) and upregulation of matrix metalloproteinase (MMP)2 and MMP9 contributed to the stimulatory effect of gonadotropins on cell migration and invasion; these effects were sufficiently blocked by a selective COX2 inhibitor. In conclusion, the present study suggests that gonadotropin-induced migration and invasion in ovarian cancer may be caused by EMT and MMP upregulation via a COX2-dependent pathway.
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Movimiento Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Gonadotropinas/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neoplasias Ováricas/patología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Invasividad Neoplásica , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We aim to determine the lncRNA targets of ΔNp63α in cervical cancer and molecular programs in cancerous differentiation. Different profiles of the lncRNAs were assayed and validated in overexpressing p63 SiHa cells (SiHa/ΔNp63α) and the control cell lines (SiHa/pCon). ENST00000422259, ENST00000447565 (Lnc-LIF-AS) and ENST00000469965, together with their related antisense mRNA DPYD (dihydropyrimidine dehydrogenase, a pyrimidine catabolic pathway gene), LIF (leukemia inhibitor factor) and FLNC (filamin C) were all notably differentially expressed in both ΔNp63α overexpression cells and knockdown cells. Here, we illustrated that ΔNp63α can inhibit the levels of LIF mRNA by direct transcription regulation and decrease LIF mRNA stability by suppressing the expression of Lnc-LIF-AS. An inverse interaction of LIF and ΔNp63α expression was as well validated in clinical samples of cervical cancer, and high level of LIF in cervical cancers was related with poor patient survival. The decrease of ΔNp63α also attenuated the differentiation of cervical cancerous cells. Suggesting that ΔNp63α may be form a complex network in regulation cervical cancerous differentiation.
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Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Factor Inhibidor de Leucemia/genética , ARN Largo no Codificante/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Neoplasias del Cuello Uterino/genética , Diferenciación Celular/genética , Línea Celular Tumoral , Dihidrouracilo Deshidrogenasa (NADP)/genética , Regulación hacia Abajo , Femenino , Filaminas/genética , Humanos , Factor Inhibidor de Leucemia/metabolismo , Unión Proteica , Análisis de Matrices Tisulares , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Regulación hacia ArribaRESUMEN
Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2',5'-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting Notably, the VACV70-triggered innate immune responses affected steroidogenesis in vivo and in vitro The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection.
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Citosol/metabolismo , ADN Viral/administración & dosificación , Células de la Granulosa/inmunología , Inmunidad Innata/inmunología , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Nucleotidiltransferasas/metabolismo , Fosfoproteínas/metabolismo , Animales , ADN Viral/química , ADN Viral/genética , Femenino , Células de la Granulosa/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Transducción de SeñalRESUMEN
The human papillomavirus (HPV) oncoproteins E6 and E7 are risk factors that are primarily responsible for the initiation and progression of cervical cancer, and they play a key role in immortalization and transformation by reprogramming differentiating host epithelial cells. It is unclear how cervical epithelial cells transform into tumor-initiating cells (TICs). Here, we observed that the germ stem cell protein Piwil2 is expressed in pre-cancerous and malignant lesions of the cervix and cervical cancer cell lines with the exception of the non-HPV-infected C33a cell line. Knockdown of Piwil2 by shRNA led to a marked reduction in proliferation and colony formation, in vivo tumorigenicity, chemo-resistance, and the proportion of cancer stem-like cells. In contrast, Piwil2 overexpression induced malignant transformation of HaCaT cells and the acquisition of tumor-initiating capabilities. Gene-set enrichment analysis revealed embryonic stem cell (ESC) identity, malignant biological behavior, and specifically, activation targets of the cell reprogramming factors c-Myc, Klf4, Nanog, Oct4, and Sox2 in Piwil2-overexpressing HaCaT cells. We further confirmed that E6 and E7 reactivated Piwil2 and that E6 and E7 overexpression resulted in a similar gene-set enrichment pattern as Piwil2 overexpression in HaCaT cells. Moreover, Piwil2 overexpression or E6 and E7 activation induced H3K9 acetylation but reduced H3K9 trimethylation, which contributed to the epigenetic reprogramming and ESC signature maintenance, as predicted previously. Our study demonstrates that Piwil2, reactivated by the HPV oncoproteins E6 and E7, plays an essential role in the transformation of cervical epithelial cells to TICs via epigenetics-based cell reprogramming.
Asunto(s)
Proteínas Argonautas/metabolismo , Carcinogénesis/genética , Papillomavirus Humano 16/genética , Células Madre Neoplásicas/fisiología , Neoplasias del Cuello Uterino/genética , Animales , Proteínas Argonautas/genética , Procesos de Crecimiento Celular/genética , Línea Celular Tumoral , Reprogramación Celular , Represión Epigenética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 4 Similar a Kruppel , Ratones , Ratones Desnudos , Células Madre Neoplásicas/virología , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , ARN Interferente Pequeño/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transcriptoma , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
High telomerase activity promotes tumor growth by stabilizing damaged chromosomes and their mitotic replication. Overactivation of telomerase activity has been reported in cervical cancer, a malignancy caused by high-risk human papillomaviruses (HR-HPVs). The HR-HPV E6 can activate hTERT promoter by interacting with E6AP or other binding proteins and by stabilizing the interaction between hTERT and E6AP. GRIM-19 is a novel tumor suppressor that affects multiple targets in a cell to regulate growth. We have previously reported the interaction of GRIM-19 with 18E6 and E6AP to disrupt the E6/E6AP complex and increase the autoubiquitination of E6AP. In this study, we characterized the interaction of GRIM-19 with 16E6 (an oncoprotein produced by HPV16) and identified the binding sites that mediate this interaction. We also found that GRIM-19 expression in cervical cancer cells could inhibit telomerase activity by inhibiting the transactivation of the hTERT promoter by E6, thereby promoting cervical cancer cell senescence. Moreover, we identified a negative correlation between GRIM-19 and hTERT expression in cervical cancer tissues. Suppression of GRIM-19 and induction of hTERT levels were associated with lymph node metastasis, advanced clinical stage, and poor prognosis. This study identified another important novel antitumor molecular link associated with GRIM-19 in the tumorigenesis.