RESUMEN
Runt-related transcription factor 2 (RUNX2) is a regulator of embryogenesis and development, but has also been implicated in the progression of certain human cancer. This study aimed to elucidate the role of RUNX2 in the invasive and metastatic potentials of human gastric cancer (GC) and the underlying mechanisms. We found that the levels of RUNX2 expression in gastric cancer tissues were correlated with the differentiation degrees, invasion depth and lymph node metastasis. COX regression analysis indicated that RUNX2 was an independent prognostic indicator for GC patients. RUNX2 significantly increased the migration and invasion ability of GC cells in vitro and enhanced the invasion and metastatic potential of GC cells in an orthotopic GC model of nude mice. Mechanistically, RUNX2 directly bound to the promoter region of the gene coding for the chemokine receptor CXCR4 to enhance its transcription. CXCR4 knockdown or treatment with AMD3100, a CXCR4 inhibitor, attenuated RUNX2-promoted invasion and metastasis. These results demonstrate that RUNX2 promotes the invasion and metastasis of human GC by transcriptionally up-regulating the chemokine receptor CXCR4. Therefore, the RUNX2-CXCR4 axis is a potential therapeutic target for GC.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Receptores CXCR4/metabolismo , Neoplasias Gástricas/patología , Animales , Apoptosis/efectos de los fármacos , Bencilaminas , Biomarcadores de Tumor/genética , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Ciclamas , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Estrogen receptor alpha 36 (ERα36), a truncated variant of ERα, is located in cytoplasm and membrane that is different from other nuclear receptors of ERα family. ERα36 is involved in progression and treatment resistance of a variety of carcinomas. However, the clinical and prognostic significance of ERα36 in renal tumors have not been fully elucidated.Here, renal tumor tissues from 125 patients were collected and immunohistochemical stained with ERα36 antibody. ERα36 expression level and location in these cases were analyzed for their correlations with clinical characteristics. The differential diagnosis value was also assessed for benign and malignant renal tumors, as well as its prognostic value.The results showed that membrane ERα36 expression was rarely detected in benign tumors but predominantly observed in malignant renal tumors. Kaplan-Meier analysis indicated that significant correlations of high ERα36 level and ERα36 membrane expression were correlated with both poor disease-free survival and overall survival. Univariate and multivariate analysis confirmed that both ERα36 high expression and membrane location can serve as unfavorable prognostic indicators for renal cell carcinoma.It is thus concluded that membrane ERα36 expression is valuable for differential diagnosis of malignant renal tumors from benign ones. Both ERα36 high expression and membrane location indicate poor prognosis in renal cell carcinoma.
Asunto(s)
Carcinoma de Células Renales/metabolismo , Receptor alfa de Estrógeno/metabolismo , Neoplasias Renales/metabolismo , Carcinoma de Células Renales/diagnóstico , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
Cancer stem cells have been isolated from various types of cancer including leukemia and solid tumors. However, the methods for isolating gastric cancer stem-like cells (GCSCs) have not been well established. As a consequence, the biological behavior and the significance of these cells to cancer progression remains to be clarified. In this study, we isolated and characterized GCSCs from a gastric cancer cell line SGC7901 and found their enhanced capabilities of invasion in vitro and metastasis in vivo. We further studied the expression of molecules related to epithelial-mesenchymal and invasion in GCSCs and found there were decreased E-cadherin, but increased vimentin and matrix metalloproteinase 2 (MMP-2), in these cells. Our results suggest that decreased E-cadherin and increased MMP-2 may be associated with the capacity of GCSCs to metastasize.