RESUMO
Ovarian cancer is the most deadly gynecological malignancy since most patients have metastatic disease at the time of diagnosis. Therefore, identification of critical pathways that contribute to ovarian cancer progression is necessary to yield novel therapeutic targets. Recently we reported that the DNA binding protein ARID3B is overexpressed in human ovarian tumors. To determine if ARID3B has oncogenic functions in vivo, ovarian cancer cell lines stably expressing ARID3B were injected intraperitoneally into nude mice. Overexpression of ARID3B increased tumor burden and decreased survival. To assess how ARID3B contributes to the increased tumor growth in vivo, we identified ARID3B induced genes in tumor ascites cells. ARID3B induced expression of genes associated with metastasis and cancer stem cells (CD44, LGR5, PROM1 (CD133), and Notch2). Moreover, ARID3B increased the number of CD133+ (a cancer stem cell marker) cells compared to control cells. The increase in CD133+ cells resulting from ARID3B expression was accompanied by enhanced paclitaxel resistance. Our data demonstrate that ARID3B boosts production CD133+ cells and increases ovarian cancer progression in vivo.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Antígeno AC133 , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Perfilação da Expressão Gênica/métodos , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Camundongos Nus , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Peptídeos/genética , Peptídeos/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ARID3B is a DNA binding protein that is overexpressed in neuroblastoma and ovarian cancer. To understand the extent that ARID3B participates in tumor development, we assessed protein expression of ARID3B in normal adult and malignant tissues. We found that ARID3B is highly expressed in differentiated layers of squamous epithelium. We also examined expression of an alternative splice form of ARID3B and found that it has similar but not identical expression patterns to the full length ARID3B isoform. ARID3B has two closely related paralogues, ARID3A and ARID3C. Each of these 3 family members exhibits different patterns of expression. Of the ARID3 family members, ARID3B is the most widely expressed and is particularly expressed in epithelium. In addition to examining normal tissue, we investigated ARID3B expression in a variety of tumor types. Most notably we found that ARID3B expression is decreased in esophagus and stomach tumors compared to normal corresponding tissues. Our results indicate that the different patterns of ARID3B in normal tissues translate into different roles for ARID3B in carcinomas.
