RESUMEN
BACKGROUND: The human endometrium is a highly dynamic tissue whose function is mainly regulated by the ovarian steroid hormones estradiol and progesterone. The serum levels of these and other hormones are associated with three specific phases that compose the endometrial cycle: menstrual, proliferative, and secretory. Throughout this cycle, the endometrium exhibits different transcriptional networks according to the genes expressed in each phase. Epigenetic mechanisms are crucial in the fine-tuning of gene expression to generate such transcriptional networks. The present review aims to provide an overview of current research focused on the epigenetic mechanisms that regulate gene expression in the cyclical endometrium and discuss the technical and clinical perspectives regarding this topic. MAIN BODY: The main epigenetic mechanisms reported are DNA methylation, histone post-translational modifications, and non-coding RNAs. These epigenetic mechanisms induce the expression of genes associated with transcriptional regulation, endometrial epithelial growth, angiogenesis, and stromal cell proliferation during the proliferative phase. During the secretory phase, epigenetic mechanisms promote the expression of genes associated with hormone response, insulin signaling, decidualization, and embryo implantation. Furthermore, the global content of specific epigenetic modifications and the gene expression of non-coding RNAs and epigenetic modifiers vary according to the menstrual cycle phase. In vitro and cell type-specific studies have demonstrated that epithelial and stromal cells undergo particular epigenetic changes that modulate their transcriptional networks to accomplish their function during decidualization and implantation. CONCLUSION AND PERSPECTIVES: Epigenetic mechanisms are emerging as key players in regulating transcriptional networks associated with key processes and functions of the cyclical endometrium. Further studies using next-generation sequencing and single-cell technology are warranted to explore the role of other epigenetic mechanisms in each cell type that composes the endometrium throughout the menstrual cycle. The application of this knowledge will definitively provide essential information to understand the pathological mechanisms of endometrial diseases, such as endometriosis and endometrial cancer, and to identify potential therapeutic targets and improve women's health.
Asunto(s)
Epigenómica/métodos , Regulación de la Expresión Génica/genética , Enfermedades Uterinas/genética , Endometrio/patología , Epigénesis Genética , Femenino , Humanos , Enfermedades Uterinas/patologíaRESUMEN
OBJECTIVES: To evaluate the expression of four genetic markers (PTEN, BCL2, MLH1, and CTNNB1), linked to endometrial carcinogenesis, in endometrial polyps of patients with and without postmenopausal bleeding in order to determine whether symptomatic endometrial polyps have a genetic phenotype similar to that of endometrial cancer. METHODS: Samples were obtained hysteroscopically from endometrial polyps of postmenopausal patients, and the expression of genetic markers involved in the pathogenesis of endometrial cancer (PTEN, BCL2, MLH1, and CTNNB1) was analyzed. The expression of these markers was then compared between patients with and without symptoms, which was characterized as postmenopausal bleeding. Other clinical characteristics of the patients, such as duration of menopause, polyp size, presence of systemic hypertension, diabetes mellitus, and smoking habits were also analyzed. RESULTS: Samples from a total of 60 patients were obtained, as calculated for a test power of 0.80. No statistical differences (p > 0.05) were observed between the two groups concerning the expression of the studied endometrial cancer risk factor genes, or with regard to the clinical aspects evaluated. CONCLUSION: The study found no evidence that symptomatic endometrial polyps have a similar phenotype to type 1 endometrial cancer; further studies are needed in order to establish whether endometrial polyps are in fact true cancer precursors, or simply raise cancer incidence due to a detection bias.
Asunto(s)
Neoplasias Endometriales/genética , Expresión Génica , Marcadores Genéticos/genética , Pólipos/genética , Posmenopausia , Enfermedades Uterinas/genética , Anciano , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Histeroscopía , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Fosfohidrolasa PTEN/genética , Pólipos/patología , Pólipos/cirugía , Proteínas Proto-Oncogénicas c-bcl-2/genética , Enfermedades Uterinas/patología , Enfermedades Uterinas/cirugía , Hemorragia Uterina , beta Catenina/genéticaRESUMEN
Several authors have investigated the malignant transformation of endometriosis, which supports the hypothesis of the pre-neoplastic state of endometriotic lesions, but there are few data about the pathways and molecular events related to this phenomenon. This review provides current data about deregulated genes that may function as key factors in the malignant transition of endometriotic lesions. In order to do so, we first searched for studies that have screened differential gene expression between endometriotic tissues and normal endometrial tissue of women without endometriosis, and found only two articles with 139 deregulated genes. Further, using the PubMed database, we crossed the symbol of each gene with the terms related to malignancies, such as cancer and tumor, and obtained 9,619 articles, among which 444 were studies about gene expression associated with specific types of tumor. This revealed that more than 68% of the analyzed genes are also deregulated in cancer. We have also found genes functioning as tumor suppressors and an oncogene. In this study, we present a list of 95 informative genes in order to understand the genetic components that may be responsible for endometriosis' malignant transformation. However, future studies should be conducted to confirm these findings.
Asunto(s)
Transformación Celular Neoplásica , Neoplasias Endometriales/genética , Endometriosis/genética , Endometriosis/patología , Enfermedades Uterinas/genética , Enfermedades Uterinas/patología , Femenino , HumanosRESUMEN
Abstract Several authors have investigated the malignant transformation of endometriosis, which supports the hypothesis of the pre-neoplastic state of endometriotic lesions, but there are few data about the pathways and molecular events related to this phenomenon. This review provides current data about deregulated genes that may function as key factors in the malignant transition of endometriotic lesions. In order to do so, we first searched for studies that have screened differential gene expression between endometriotic tissues and normal endometrial tissue of women without endometriosis, and found only two articles with 139 deregulated genes. Further, using the PubMed database, we crossed the symbol of each gene with the terms related to malignancies, such as cancer and tumor, and obtained 9,619 articles, among which 444 were studies about gene expression associated with specific types of tumor. This revealed that more than 68% of the analyzed genes are also deregulated in cancer. We have also found genes functioning as tumor suppressors and an oncogene. In this study, we present a list of 95 informative genes in order to understand the genetic components that may be responsible for endometriosis' malignant transformation. However, future studies should be conducted to confirm these findings.
Resumo Vários autores têm estudado transformações malignas em endometriose que suportam a hipótese de um estado pré-neoplásico das lesões endometrióticas; contudo, existem poucos dados sobre as vias e eventos moleculares relacionados a este fenômeno. Esta revisão fornece dados atuais sobre genes desregulados que possam funcionar como fatores-chave para a transição maligna das lesões endometrióticas. Assim, inicialmente, estudos de expressão gênica diferencial em larga escala comparando tecido endometriótico e endométrio normal de mulheres sem endometriose foram procurados, e apenas dois artigos com 139 genes desregulados foram obtidos. Posteriormente, usando o banco de dados do PubMed, foram cruzados os símbolos de cada gene com termos relacionados à malignidade, como câncer e tumor, e 9.619 artigos foram obtidos, dos quais 444 eram estudos sobre expressão de genes associados a tipos específicos de tumor. Isto revela que mais de 68% dos genes analisados eram também desregulados em câncer. Também foram encontrados genes que funcionam como supressor tumoral e um oncogene. Este estudo apresenta uma lista de 95 genes informativos para compreender os componentes genéticos que possam ser responsáveis por transformações malignas na endometriose. Contudo, estudos futuros são necessários para confirmar estes achados.
Asunto(s)
Humanos , Femenino , Transformación Celular Neoplásica , Neoplasias Endometriales/genética , Endometriosis/genética , Endometriosis/patología , Enfermedades Uterinas/genética , Enfermedades Uterinas/patologíaRESUMEN
OBJECTIVE: To establish whether human fallopian tube (FT) epithelium can induce apoptosis in T lymphocytes and endometrial cells. DESIGN: Laboratory-based study. SETTING: Hospital. PATIENT(S): Women undergoing abdominal hysterectomy for FT samples, and women volunteers with and without endometriosis for endometrial biopsies. INTERVENTION(S): FT samples obtained at time of surgery performed in reproductive-aged women with normal menstrual cycles. MAIN OUTCOME MEASURE(S): T lymphocytes or endometrial cells coincubated with FT epithelial cells and assayed for apoptosis by DNA nick-end labeling and caspase-3 activity, with the presence of Fas ligand (FasL) and Fas receptor (FasR) assessed by indirect immunostaining. RESULT(S): The epithelium of the FT-induced apoptosis in T cells as well as in human endometrial cells. The mechanism probably involves the FasL/FasR system; accordingly, we observed FasL at the apical surface of the epithelium and in the stroma of the FT at all phases of the menstrual cycle except during the early proliferative phase. The endometrial samples from patients with endometriosis did not express FasR and were resistant to apoptosis. CONCLUSION(S): In both FasR(+) T lymphocytes and endometrial cells, FasL(+) FT cells induce apoptosis. Data suggest that the FT epithelium acts as a barrier to limit the influx of lymphocytes as well as endometrial cells ascending the tube. Failure of these regulatory mechanisms may be related to the development of endometriosis.
Asunto(s)
Apoptosis , Endometrio/fisiología , Trompas Uterinas/fisiología , Proteína Ligando Fas/metabolismo , Linfocitos T/fisiología , Receptor fas/metabolismo , Adulto , Apoptosis/genética , Apoptosis/inmunología , Apoptosis/fisiología , Caspasa 3/metabolismo , Células Cultivadas , Endometriosis/genética , Endometriosis/metabolismo , Endometriosis/patología , Endometrio/citología , Endometrio/metabolismo , Endometrio/patología , Epitelio/metabolismo , Epitelio/patología , Epitelio/fisiología , Femenino , Humanos , Enfermedades Peritoneales/genética , Enfermedades Peritoneales/metabolismo , Enfermedades Peritoneales/patología , Linfocitos T/metabolismo , Enfermedades Uterinas/genética , Enfermedades Uterinas/metabolismo , Enfermedades Uterinas/patologíaRESUMEN
AIMS: The aim of this study was to evaluate urokinase-type plasminogen activator gene (uPA) and thrombin-activatable fibrinolysis inhibitor gene (TAFI) genotypes in a group of infertile women with and/or without endometriosis and controls. METHODS: A case-control study comprising 180 infertile women with endometriosis, 68 women with idiopathic infertility, and 152 fertile women as controls was carried out. Detection of uPA (C422T/rs2227564) and TAFI (G438A/rs2146881) polymorphisms was performed by TaqMan polymerase chain reaction. The results were statistically analyzed and a p-value of <0.05 was considered significant. RESULTS: We found no association among both uPA or TAFI polymorphisms and endometriosis-related infertility (p=0.920 and p=0.356, respectively) or idiopathic infertility (p=0.502 and p=0.392, respectively) comparing to controls, even considering minimal/mild and moderate/severe endometriosis separately. Both uPA and TAFI polymorphisms were in Hardy-Weinberg equilibrium for all studied groups. The combinatory analysis of both uPA and TAFI polymorphisms to endometriosis-related infertility, idiopathic infertility, and control group showed no statistical difference to any combination. CONCLUSION: The data suggest that, in the Brazilian population, genetic variations in both uPA and TAFI were not relevant to endometriosis and/or infertility.
Asunto(s)
Endometriosis/genética , Fibrinólisis/genética , Variación Genética , Infertilidad Femenina/genética , Enfermedades Uterinas/genética , Adulto , Brasil , Carboxipeptidasa B2/genética , Estudios de Casos y Controles , Endometriosis/complicaciones , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Variación Genética/fisiología , Genotipo , Humanos , Infertilidad Femenina/complicaciones , Redes y Vías Metabólicas/genética , Polimorfismo Genético , Índice de Severidad de la Enfermedad , Activador de Plasminógeno de Tipo Uroquinasa/genética , Enfermedades Uterinas/complicacionesRESUMEN
OBJECTIVE: To evaluate the expression pattern of activin A, activin receptors, and activin modulators messenger RNA (mRNA) in the eutopic endometrium of patients with endometriosis at different phases of the menstrual cycle and to evaluate the mRNA expression of the same proteins in endometriomas during the menstrual cycle. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Women with and without endometriosis. INTERVENTION(S): Samples of endometrial and endometriotic tissue from women with endometrioma (n=48), and endometrial samples from women without endometriosis (controls) (n=48). MAIN OUTCOME MEASURE(S): Quantification of activin A, activin B, activin receptor II, nodal, cripto, inhibin α, and follistatin expression by real-time reverse-transcriptase polymerase chain reaction (RT-PCR). RESULT(S): The eutopic endometrium of patients with endometriosis showed [1] higher activin A mRNA expression in the proliferative phase and a lack of late secretory phase peak, [2] a lack of endometrial cycle-related variations of cripto and inhibin α mRNA expression, and [3] an inverse expression pattern of follistatin mRNA. Endometriomas showed similar variations in the expression of activin-related protein mRNA during the menstrual cycle as eutopic endometrium. CONCLUSION(S): The disturbed expression of endometrial activin A, cripto (activin receptor antagonist), and follistatin (activin-binding protein) suggests a dysfunction of the activin pathway in endometriosis. Endometriomas showed similar changes of activin-related proteins during the menstrual cycle, which supports a common biology for eutopic and ectopic endometrium in endometriosis.
Asunto(s)
Activinas/genética , Endometriosis/genética , Folistatina/genética , Proteínas Ligadas a GPI/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de Neoplasias/genética , Enfermedades Uterinas/genética , Receptores de Activinas Tipo II/genética , Adulto , Análisis de Varianza , Brasil , Estudios de Casos y Controles , Endometriosis/patología , Endometriosis/fisiopatología , Femenino , Regulación Neoplásica de la Expresión Génica , Hospitales Universitarios , Humanos , Inhibinas/genética , Ciclo Menstrual , Estudios Prospectivos , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Enfermedades Uterinas/patología , Enfermedades Uterinas/fisiopatología , Adulto JovenRESUMEN
Estrogens are important factors in the development of endometriosis, and can induce cell proliferation and stimulate cell division. COMT constitutes a crucial element in estrogen metabolism and has been suggested to be involved in the development of endometriosis. This study had the objective of to determine whether the presence of COMT val/met polymorphism (rs4680) increases the risk to endometriosis in infertile patients. A case-control study that included 198 infertile women with endometriosis, 71 infertile women without endometriosis, and 168 fertile women as control group of the Faculdade de Medicina do ABC. COMT (val/met) genotypes were identified by real time PCR (genotyping TaqMan assay) and the results were analyzed statistically by χ² test. The data showed no statistical difference in the distribution of COMT genotypes neither between infertile patients with endometriosis and control group (p = 0.567), regardless disease degree, nor between infertile patients without endometriosis and control group (p = 0.460). In conclusion, the COMT val/met polymorphism is not associated to endometriosis-related infertility in the Brazilian population evaluated. However, more studies in larger populations are necessary to confirm these results.
Asunto(s)
Catecol O-Metiltransferasa/genética , Endometriosis/complicaciones , Infertilidad Femenina/genética , Polimorfismo de Nucleótido Simple/fisiología , Enfermedades Uterinas/complicaciones , Adulto , Brasil , Estudios de Casos y Controles , Catecol O-Metiltransferasa/fisiología , Endometriosis/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Infertilidad Femenina/etiología , Desequilibrio de Ligamiento , Factores de Riesgo , Índice de Severidad de la Enfermedad , Enfermedades Uterinas/genéticaRESUMEN
PURPOSE: To evaluate the clinical and epidemiological risk factors for endometrial cancer in postmenopausal women with endometrial polyps, as well as the genetic polymorphism of the progesterone receptor (PROGINS). METHODS: A case-control study was designed with 160 postmenopausal women with endometrial polyps, compared to a normal Control Group of 400 postmenopausal women. The genotyping of PROGINS polymorphism was determined by the polymerase chain reaction. Clinical and epidemiological data were compared between benign endometrial polyps and 118 of the control subjects. Variables were also compared with regard to benign and malignant endometrial polyps. RESULTS: Comparison of the epidemiological variables between groups showed a significant difference for age, ethnicity, time since menopause, parity, tamoxifen use, hypertension and breast cancer, all of them more prevalent in the polyp group. After adjustment for age, statistical significance remained only for parity (OR=1.1), hypertension (OR=2.2) and breast cancer (OR=14.4). There were six cases of malignant polyps (3.7%). The frequency of bleeding was 23.4% for benign polyps and 100% for malignant polyps, with large polyps being detected in 54.6% of the benign cases and in 100 of the malignnat ones. The frequency of arterial hypertension was 54.5% for benign polyps and 83.3% for the malignant ones. The frequency of PROGINS T1/T1, T1/T2 and T2/T2 polymorphism was 79.9%, 19.5% and 0.6%, respectively, for the polyp group, and 78.8%, 20.8% and 0.5% for the Control Group. CONCLUSIONS: Elderly age, hypertension, and breast cancer were significantly associated with endometrial polyps. The presence of PROGINS polymorphism was not significantly associated with endometrial polyps. The incidence of malignant polyps was low and strongly associated with bleeding, large-sized polyp and arterial hypertension.
Asunto(s)
Polimorfismo Genético , Pólipos/genética , Receptores de Progesterona/genética , Enfermedades Uterinas/genética , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Pólipos/diagnóstico , Pólipos/epidemiología , Estudios Prospectivos , Enfermedades Uterinas/diagnóstico , Enfermedades Uterinas/epidemiologíaRESUMEN
OBJECTIVE(S): To investigate the prevalence of microsatellite instability (MSI) in endometrial polyps and to evaluate whether there are clinical and histopathological parameters associated with this kind of instability. STUDY DESIGN: Between September 2008 and April 2009, endometrial polyps were collected from 109 patients. MSI was evaluated using the NCI recommended markers BAT25, BAT26, D2S123, D5S346 and D17S250. Histopathological analysis was performed, and clinical information was obtained from patients' records. RESULT(S): MSI low was detected in 6.4% of the validated samples (7/109). Of the seven MSI that were detected, six were positive for instability at D17S250 and one at D5S346. There were no significant differences between polyps with or without MSI with regard to age, BMI, menarche, parity, miscarriage or menopause; however, MSI was more frequent in polyps with simple hyperplasia without atypia (3/20; 15%). Furthermore, patients with multiple polyps had a marginally but statistically insignificant increase in the frequency of MSI (p<0.07). CONCLUSION(S): This is the first prospective study of MSI in endometrial polyps using hysteroscopically obtained samples. In a population of 109 patients, MSI was infrequent in endometrial polyps. Although MSI appears to be more frequent in multiple polyps and polyps with simple hyperplasia without atypia, this was not statistically significant.
Asunto(s)
Neoplasias Endometriales/genética , Inestabilidad de Microsatélites , Pólipos/genética , Enfermedades Uterinas/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Pólipos/patología , Enfermedades Uterinas/patologíaRESUMEN
OBJETIVO: avaliar as variáveis clínicas e epidemiológicas de risco para câncer de endométrio em mulheres com pólipos endometriais na pós-menopausa, bem como a presença do polimorfismo do receptor da progesterona (PROGINS). MÉTODOS: estudo caso-controle desenhado com 160 mulheres na pós-menopausa com pólipos endometriais, comparado a Grupo Controle de 400 mulheres na pós-menopausa. A genotipagem do polimorfismo PROGINS foi determinada pala reação em cadeia da polimerase (PCR). Aspectos clínicos e epidemiológicos foram comparados entre as mulheres com pólipos endometriais benignos e 118 dos controles normais. Estas variáveis foram também comparadas entre mulheres com pólipos benignos e pólipos malignos. RESULTADOS: a comparação entre o grupo de pólipos benignos e o Grupo Controle mostrou diferença significativa (p<0,05) para as varáveis: idade, raça não-branca, anos da menopausa, paridade, hipertensão arterial, uso de tamoxifeno e antecedente de câncer de mama, todas mais prevalentes no grupo de pólipos endometriais. Após o ajuste para a idade, permaneceram com diferença significativa a paridade (OR=1,1), hipertensão arterial (OR=2,2) e o antecedente de câncer de mama (OR=14,4). Houve seis casos de pólipos malignos (3,7 por cento). A frequência de sangramento para pólipos benignos e malignos foi de 23,4 e 100 por cento, respectivamente, sendo o pólipo grande encontrado em 54,5 por cento dos casos benignos e em 100 por cento dos malignos. A frequência de hipertensão arterial foi de 54,5 por cento para pólipos benignos e 83,3 por cento para pólipos malignos. As frequências do polimorfismo PROGINS T1/T1, T1/T2 e T2/T2 foram 79,9 por cento, 19,5 por cento e 0,6 por cento respectivamente para pólipos benignos e 78,8 por cento, 20,8 por cento e 0,5 por cento para o Grupo Controle. CONCLUSÕES: os pólipos endometriais se mostraram mais frequentes em mulheres de idade avançada, hipertensas e com antecedente de câncer de mama. A presença do polimorfismo PROGINS não mostrou associação significativa com pólipos endometriais. A incidência de pólipos malignos foi baixa, estando fortemente associada à presença de sangramento, tamanho grande do pólipo e hipertensão arterial.
PURPOSE: to evaluate the clinical and epidemiological risk factors for endometrial cancer in postmenopausal women with endometrial polyps, as well as the genetic polymorphism of the progesterone receptor (PROGINS). METHODS: a case-control study was designed with 160 postmenopausal women with endometrial polyps, compared to a normal Control Group of 400 postmenopausal women. The genotyping of PROGINS polymorphism was determined by the polymerase chain reaction. Clinical and epidemiological data were compared between benign endometrial polyps and 118 of the control subjects. Variables were also compared with regard to benign and malignant endometrial polyps. RESULTS: comparison of the epidemiological variables between groups showed a significant difference for age, ethnicity, time since menopause, parity, tamoxifen use, hypertension and breast cancer, all of them more prevalent in the polyp group. After adjustment for age, statistical significance remained only for parity (OR=1.1), hypertension (OR=2.2) and breast cancer (OR=14.4). There were six cases of malignant polyps (3.7 percent). The frequency of bleeding was 23.4 percent for benign polyps and 100 percent for malignant polyps, with large polyps being detected in 54.6 percent of the benign cases and in 100 of the malignnat ones. The frequency of arterial hypertension was 54.5 percent for benign polyps and 83.3 percent for the malignant ones. The frequency of PROGINS T1/T1, T1/T2 and T2/T2 polymorphism was 79.9 percent, 19.5 percent and 0.6 percent, respectively, for the polyp group, and 78.8 percent, 20.8 percent and 0.5 percent for the Control Group. CONCLUSIONS: elderly age, hypertension, and breast cancer were significantly associated with endometrial polyps. The presence of PROGINS polymorphism was not significantly associated with endometrial polyps. The incidence of malignant polyps was low and strongly associated with bleeding, large-sized polyp and arterial hypertension.
Asunto(s)
Femenino , Humanos , Persona de Mediana Edad , Polimorfismo Genético , Pólipos/genética , Receptores de Progesterona/genética , Enfermedades Uterinas/genética , Estudios de Casos y Controles , Estudios Prospectivos , Pólipos/diagnóstico , Pólipos/epidemiología , Enfermedades Uterinas/diagnóstico , Enfermedades Uterinas/epidemiologíaRESUMEN
OBJECTIVE: To evaluate the role of nuclear factor-κB (NF-κB) in the pathogenesis of endometriosis. DESIGN: A literature search was conducted in PubMed to identify all relevant citations. RESULT(S): Our findings highlight the important role of NF-κB in the pathophysiology of endometriosis. In vitro and in vivo studies show that NF-κB-mediated gene transcription promotes inflammation, invasion, angiogenesis, and cell proliferation and inhibits apoptosis of endometriotic cells. Constitutive activation of NF-κB has been demonstrated in endometriotic lesions and peritoneal macrophages of endometriosis patients. Agents blocking NF-κB are effective inhibitors of endometriosis development and some drugs with known NF-κB inhibitory properties have proved efficient at reducing endometriosis-associated symptoms in women. Iron overload activates NF-κB in macrophages. NF-κB activation in macrophages and ectopic endometrial cells stimulates synthesis of proinflammatory cytokines, generating a positive feedback loop in the NF-κB pathway and promoting endometriotic lesion establishment, maintenance and development. CONCLUSION(S): NF-κB transcriptional activity modulates key cell processes contributing to the initiation and progression of endometriosis. Because endometriosis is a multifactorial disease, inhibiting NF-κB appears to be a promising strategy for future therapies targeting different cell functions involved in endometriosis development, such as cell adhesion, invasion, angiogenesis, inflammation, proliferation, and apoptosis. Upcoming research will elucidate these hypotheses.
Asunto(s)
Endometriosis/etiología , FN-kappa B/fisiología , Enfermedades Uterinas/etiología , Animales , Endometriosis/genética , Endometriosis/inmunología , Endometriosis/metabolismo , Femenino , Humanos , Inflamación/complicaciones , Modelos Biológicos , FN-kappa B/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Enfermedades Uterinas/genética , Enfermedades Uterinas/inmunología , Enfermedades Uterinas/metabolismoRESUMEN
Endometriosis is a benign gynecological pathology in which immune system deregulation may play a role in its initiation and progression. In endometriotic lesions, intercellular adhesion molecule-1 (ICAM1) is released from the cell membrane by proteolytic cleavage of its extracellular domain, a process that coincides with increased expression and proteolytic activity of metalloproteinases such as MMP1 and MMP9. The objective of our study was to investigate the association between MMP1 and MMP9 activities and ICAM1 cleavage mediated by tumor necrosis factor (TNF) in eutopic endometrial stromal cells from women with and without (control) endometriosis during culture. The RNA was evaluated by RT-PCR, and the protein was determined by western blot (ICAM1, MMP1), casein or gelatin zymographies (secreted active MMP1 or MMP9 respectively), ELISA (soluble ICAM1 (sICAM1)), and fluorescence assay (secreted active MMP1). Under basal conditions, proMMP9 dimer and MMP9 were higher in endometriosis cell cultures. In stromal cultures derived from control women and those with endometriosis, TNF augmented the intracellular proMMP1 (1.2-fold in control stromal cells) and ICAM1 (1.4- and 1.9-fold), greatly increased MMP1 and proMMP9 levels, and the sICAM1 concentration (2.3- and 4.3-fold) in their media compared with basal levels. The combination of TNF and MMP9 increased the sICAM1 concentration 14-fold in the endometriosis cell media, whereas GM6001 inhibited the stimulatory effect of TNF in both cell cultures. The deregulation of MMP9, and the TNF participation in the MMP1 and proMMP9 secretions, in the MMP9 expression and in the expression and cleavage of ICAM1 may contribute to the pathophysiology of this disease.
Asunto(s)
Endometriosis/patología , Endometrio/patología , Molécula 1 de Adhesión Intercelular/metabolismo , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Células del Estroma/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Enfermedades Uterinas/patología , Adulto , Estudios de Casos y Controles , Células Cultivadas , Endometriosis/genética , Endometriosis/metabolismo , Endometrio/efectos de los fármacos , Endometrio/metabolismo , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Activación Enzimática/fisiología , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/genética , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Cultivo Primario de Células , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Células del Estroma/metabolismo , Células del Estroma/patología , Enfermedades Uterinas/genética , Enfermedades Uterinas/metabolismoRESUMEN
OBJECTIVE: To analyze solitary bone fragments from the uterine cavity through DNA genotyping, thus elucidating whether they originate from metaplasia, from previous abortion, or both. METHODS: We conducted a case series study on 14 patients, of whom eight yielded bone DNA. The patients selected had histopathologic diagnoses of bone fragments inside the uterine cavity or previously removed samples available for analysis. We extracted DNA from blood and bone fragments. To identify the bone tissue origin, these materials were genotyped using polymerase chain reactions for DNA loci. Six mini short tandem repeat loci frequently used for human tissue identification were analyzed using automated sequencing. RESULTS: Among these eight patients, blood and tissue samples from the same individual produced exactly the same pair of alleles for all six loci. This indicated that the DNA profile was completely the same for the bone samples and the mother's blood (95% confidence interval 63-100%), thus confirming that the DNA had the same origin and that these were cases of metaplasia. CONCLUSION: In all of the eight cases, bone formation was caused by osseous metaplasia, because the DNA in the bone fragment and in the patient's blood was identical. Although all of the women had histories of previous abortion, no difference in DNA was detected in the bone tissue in any of the cases, as would be expected if abortion had occurred. This result was completely unexpected, differing greatly from what the literature suggests. LEVEL OF EVIDENCE: III.