RESUMEN
OBJECTIVE@#To analyze the expression of immunoglobulin mucin molecule 3 (TIM-3) in epithelial ovarian cancer (EOC) and the effects of TIM-3 knockdown and overexpression on proliferation and migration of ovarian cancer cells.@*METHODS@#We analyzed TIM-3 expression in EOC and normal ovarian tissues using GEPIA database. We also detected TIM-3 expression levels in 82 surgical specimens of EOC and 18 specimens of normal ovarian tissues using immunohistochemistry, and analyzed the correlation of TIM-3 expression with clinicopathological parameters and survival outcomes of the patients. The expression of TIM-3 and Wnt1 mRNA in the tissues were detected using qRT-PCR. We constructed SKOV3 cell models of TIM-3 knockdown and overexpression and examined the changes in proliferation, apoptosis, migration and invasion of the cells using MTT assay, Annexin V-FITC/PI staining, scratch test and Transwell assay. The activity of Wnt/β-catenin pathway in the transfected was detected using dual luciferase reporter assay, and the mRNA levels of TCF-7, TCCFL-2 and CD44 were detected using qPCR. The protein expressions of MMP-9, CD44, Wnt1, β-catenin and E-cad in the transfected cells were detected with Western blotting.@*RESULTS@#The positive expression rate of TIM-3 was significantly higher in EOC tissues than in normal ovarian tissues (P < 0.05). The expression of TIM-3 was significantly correlated with FIGO stage, histological differentiation and lymph node metastasis, and was positively correlated with Wnt1 level (P < 0.05). In SKOV3 cells, TIM-3 knockdown significantly lowered the activity of Wnt/ β-catenin pathway, inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. TIM-3 knockdown significantly down-regulated the mRNA levels of TCF-7, TCFL-2 and CD44 and the protein levels of MMP-9, CD44, Wnt1 and β-catenin, and significantly up-regulated the expression level of E-cad (P < 0.05). Overexpression of TIM-3 caused opposite effects in SKOV3 cells.@*CONCLUSION@#TIM-3 is highly expressed in EOC tissue to promote malignant behaviors of the tumor cells possibly by activating the Wnt/β-catenin signal pathway.
Asunto(s)
Femenino , Humanos , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Neoplasias Ováricas/metabolismoRESUMEN
Resumen El cáncer de ovario ocupa el tercer lugar en frecuencia entre los cánceres ginecológicos en Argentina. Existe un déficit de información de esta enfermedad en nuestro país respecto al tratamiento y evolución oncológica de las pacientes. El objetivo de nuestro trabajo fue evaluar los resultados perioperatorios y oncológicos, en pacientes con tumor epitelial de ovario con estadios avanzados. Presentamos una cohorte retrospectiva en la que se evaluó la supervivencia libre de enfermedad y la supervivencia global en pacientes con tumores epiteliales de ovario tratadas en el Hospital Italiano de Buenos Aires entre junio del 2009 a junio del 2017. De 170 pacientes incluidas en el estudio, 72 (42.4%) fueron tratadas con una cirugía de citorreducción primaria (CCP), mientras que 98 (57.6%) recibieron neoadyuvancia y luego cirugía del intervalo (CI). La tasa de citorreducción óptima fue de 75% y de 79% respectivamente. No se encontraron diferencias en los resultados perioperatorios, ni en las complicaciones graves entre ambos grupos. La mediana de SLE en el grupo de CCP fue de 2.5 años (IC 95% 1.6-3.1) mientras que en el grupo de CI fue de 1.4 (IC 95% 1.2-1.7) p < 0.001. La mediana de supervivencia global fue de 5.8 años en CCP, y de 3.5 años en CI. En pacientes adecuadamente seleccionadas la CCP presenta mejores resultados oncológicos a la neoadyuvancia y CI. La selección correcta de las pacientes para tratamiento primario es fundamental para definir la conducta terapéutica.
Abstract Ovarian cancer represents the third gynecological cancer in frequency in Argentina. There is a lack of information on this pathology in our country regarding the treatment and evolution of patients who suffer it. The aim of this study was to evaluate the perioperative and oncological results in patients with advanced epithelial ovarian tumor. We present a retrospective cohort in which we evaluated disease-free survival and overall survival in patients with epithelial ovarian tumor treated at the Hospital Italiano de Buenos Aires between June 2009 and June 2017. Of 170 patients included in the study, 72 (42.4%) received primary debulking surgery (CCP), while 98 (57.6%) received neoadjuvant therapy and interval surgery (CI). The optimal cyto-reduction rate was 75% and 79% respectively. No differences were found in perioperative outcomes, or in severe complications between the two groups. The median disease-free survival in the CCP group was 2.5 years (95% CI 1.6-3.1) while in the CI group it was 1.4 (95% CI 1.2-1.7) p < 0.001. The median overall survival was 5.8 years in CPP, and 3.5 years in CI. Faced with a meticulous selection by a group of experts, patients with advanced ovarian cancer treated with CCP present better oncological results than those who received neoadjuvant therapy and CI.
Asunto(s)
Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Estudios Retrospectivos , Resultado del Tratamiento , Terapia Neoadyuvante , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/terapia , Hospitales , Estadificación de NeoplasiasRESUMEN
Cáncer epitelial de ovario es una enfermedad altamente letal. Constituye la quinta causa de muerte por cáncer en mujeres a nivel mundial. El subtipo histológico más frecuente es el carcinoma seroso de alto grado. Este es el responsable de la alta letalidad de la enfermedad. Se presenta evidencia que respalda el origen tubario de este tipo histológico desde lesiones precursoras. A partir de estos datos se ha establecido que el cáncer tradicionalmente conocido como cáncer ovárico seroso de alto grado, el cáncer de trompa de Falopio y el carcinoma peritoneal primario, corresponden a una misma entidad nosológica: cáncer seroso pélvico de alto grado. Se revisa además la evidencia disponible para establecer que la salpingectomía podría constituir una medida de prevención para este tipo de cáncer.
Epithelial ovarian cancer is a highly lethal disease. It is the 5th cause of cancer death in women worldwide. The most common histologic subtype is the high-grade serous carcinoma. This is the responsible for the high lethality of the disease. Evidence supporting the tubal origin of this histological type from precursor lesions is presented. From these data it has been established that cancer traditionally known as serous high-grade ovarian cancer, cancer of the fallopian tube and primary peritoneal carcinoma, correspond to a single disease entity: pelvic serous high-grade cancer. We also check the available evidence to establish that the salpingectomy could be a preventive measure for this type of cancer.