RESUMEN
OBJECTIVE: The Runt domain transcription factor, RUNX3, has been shown to be a tumor suppressor in a variety of cancers including gastric, colon and breast cancer. Interestingly, an oncogenic role for RUNX3 has also been suggested in basal cell carcinoma and head and neck cancer. Here, we explore the role of RUNX3 in ovarian cancer. METHODS: Expression of RUNX3 mRNA and protein was evaluated in human ovarian cancer cell lines. In addition, subcellular localization of RUNX3 was also examined in cell lines and ovarian cancer tissues. Effect of exogenous RUNX3 expression and knockdown on cell proliferation was investigated by proliferation assays and a soft agar assay. RESULTS: Expression of RUNX3 was detected in the nucleus of ovarian cancer cell lines and ovarian cancer tissues and was found to play a growth stimulatory role. RUNX3 knockdown resulted in a decrease in cell proliferation in liquid media as well as in soft agar. Despite the fact that exogenous expression of RUNX3 strongly inhibits cell growth in many cell types, RUNX3 promoted cell growth in ovarian cancer cell lines not expressing RUNX3. CONCLUSION: RUNX3 is frequently expressed in the nuclei of ovarian cancer cell lines and plays an oncogenic role in ovarian cancer.
Asunto(s)
Subunidad alfa 3 del Factor de Unión al Sitio Principal/fisiología , Oncogenes , Neoplasias Ováricas/etiología , Línea Celular Tumoral , Subunidad alfa 3 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patologíaRESUMEN
Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-beta) superfamily, are multifunctional cytokines regulating a broad spectrum of biological functions. Recent studies show the presence of BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer, suggesting that aberrations in BMP signaling play an important role in intestinal cancer pathogenesis. However, the exact molecular mechanisms remain poorly understood. The Runt domain transcription factor RUNX3 is an integral component of signaling pathways mediated by TGF-beta and BMPs. RUNX3 is a gastric and colon tumor suppressor, functioning downstream of TGF-beta. Recently, we showed the tumor-suppressive effects of RUNX3 by its ability to attenuate beta-catenin/T-cell factors (TCFs) transactivation in intestinal tumorigenesis. Here, we explore the molecular basis of the tumor-suppressive function of the BMP pathway through RUNX3 in colorectal carcinogenesis. BMP exerted a growth-suppressive effect in HT-29, a human colorectal cancer cell line. c-Myc oncogene was found to be downregulated by BMP and/or RUNX3. We show that upregulation of RUNX3 by BMP reduces c-Myc expression. Evidence is presented suggesting that RUNX3 downregulates c-Myc expression by two parallel pathways-directly at the transcriptional level and through attenuation of beta-catenin/TCFs, downstream of BMPs in colorectal cancer cells.
Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Neoplasias Colorrectales/metabolismo , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Transducción de Señal , Apoptosis , Western Blotting , Proteínas Morfogenéticas Óseas/genética , Línea Celular Tumoral , Proliferación Celular , Inmunoprecipitación de Cromatina , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción TCF/genética , Factores de Transcripción TCF/metabolismo , Transcripción Genética , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
In intestinal epithelial cells, inactivation of APC, a key regulator of the Wnt pathway, activates beta-catenin to initiate tumorigenesis. However, other alterations may be involved in intestinal tumorigenesis. Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex with beta-catenin/TCF4 and attenuates Wnt signaling activity. A significant fraction of human sporadic colorectal adenomas and Runx3(+/-) mouse intestinal adenomas showed inactivation of RUNX3 without apparent beta-catenin accumulation, indicating that RUNX3 inactivation independently induces intestinal adenomas. In human colon cancers, RUNX3 is frequently inactivated with concomitant beta-catenin accumulation, suggesting that adenomas induced by inactivation of RUNX3 may progress to malignancy. Taken together, these data demonstrate that RUNX3 functions as a tumor suppressor by attenuating Wnt signaling.