RESUMEN
RIPK4 has been implicated in multiple cancer types, but its role in ovarian cancer (OC) has not been clearly elucidated. Our data from Gene Expression Profiling Interactive Analysis, RT-PCR, and immunohistochemical analysis showed that RIPK4 was expressed at higher levels in OC tissues and cells than in normal ovarian tissues and cells. Increased RIPK4 expression in OC markedly correlated with a worse overall survival than lower RIPK4 expression levels (hazard rate (HR) 1.5 (1.45-1.87); P = 0.001). In functional experiments, RIPK4 downregulation significantly inhibited metastatic behaviours in OC cells. Subsequently, based on data from 593 OC patients in the TCGA database, gene set enrichment analysis revealed that RIPK4 was involved in epithelial-mesenchymal transition (EMT) in OC. At the molecular level, silencing RIPK4 significantly downregulated vimentin, N-cadherin, and Twist expression but induced an increase in the protein level of E-cadherin and inhibited the IL-6 and STAT3 levels. Moreover, IL-6 levels were significantly decreased in RIPK4-silenced OC cells (P < 0.05). The addition of IL-6 to OC cells rescued the suppressive effect of RIPK4 knockdown on EMT. Thus, our data illustrate that downregulation of RIPK4 expression can restrain EMT in OC by inhibiting IL-6. This finding may provide a novel diagnostic and therapeutic target for improving the poor prognoses of OC patients.
Asunto(s)
Carcinoma Epitelial de Ovario/inmunología , Transición Epitelial-Mesenquimal/inmunología , Interleucina-6/metabolismo , Neoplasias Ováricas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Biología Computacional , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Proteínas Serina-Treonina Quinasas/genética , Regulación hacia Arriba/inmunología , Adulto JovenRESUMEN
Objective To investigate the prognostic significance of and risk factors for solitary lymph node metastasis (SLNM) of patients with cervical carcinoma. Methods Clinical data from patients with International Federation of Gynecology and Obstetrics (FIGO) stages IA2 to IIA cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy between January 2003 and December 2010 were analysed retrospectively. Histopathological analysis was used to identify SLNM. Long-term survival and risk factors associated with SLNM were analysed. Results The study enrolled 302 patients with cervical cancer: 48 with SLNM (SLNM group) and 254 patients with no lymph node metastases (nLNM group). FIGO stage, tumour grade, depth of tumour invasion, uterine body involvement, parametrial involvement and lymphovascular invasion differed significantly between the two groups. Logistic regression analysis revealed that FIGO stage, depth of tumour invasion and lymphovascular invasion were independent factors associated with SLNM. The 5-year survival rates of the SLNM and nLNM groups were 54.2% and 87.8%, respectively. Multivariate analysis identified SLNM as an independent factor affecting survival. Conclusions The occurrence of just one solitary lymph node metastasis significantly worsened the prognosis in patients with cervical carcinoma compared with patients without lymph node metastases.
Asunto(s)
Ganglios Linfáticos/patología , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , Adulto , Supervivientes de Cáncer/estadística & datos numéricos , Femenino , Humanos , Histerectomía , Escisión del Ganglio Linfático , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Neoplasias del Cuello Uterino/cirugíaRESUMEN
Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/- mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma.
