AbstractsBiology & Animal Science

The transcription factor SOX2 is a key determinant of stem cell properties, also involved in the initiation, maintenance and progression of several human cancers. By studying the in vitro phenotypic consequences of SOX2 overexpression and knock down in a panel of cell lines, we have found that high levels of SOX2 leads to DNA damage and accumulation of reactive oxygen species, accompanied with cell cycle arrest and apoptosis in colorectal cancer cell lines, SW620 and SW480. We have also found that knock down of SOX2 in the metastatic colorectal cancer cell line SW620, led to G1 cell cycle arrest partially dependent on the cyclin-dependent kinase inhibitors p21 and p27, as well as abrogation of anchorage-independent growth in vitro and tumor growth in vivo. Knock down of SOX2 caused the upregulation of p27 and reporter assays combining knock down and overexpression of this transcription factor suggest that SOX2 may act as a negative transcriptional regulator of p27. Knock down of p27 partially reverted the cell-cycle arrest induced by SOX2 repression but was insufficient to restore anchorage-independent growth in vitro. In addition, it also led to downregulation of LGR5 transcript levels, a known intestinal stem cell marker, but it is unknown whether this regulation is mediated directly by SOX2 or by other mechanisms. Knock down of LGR5 partially phenocopied the repression of SOX2 in SW620 cells; it abrogated their anchorage-independent growth in vitro and tumor growth in vivo, in spite of a strong induction of β-catenin transcriptional activity. Activation of β-catenin transcriptional activity upon LGR5 knock down was paralleled by decreased membrane association and enhanced nuclear translocation but not by β-catenin protein accumulation or downregulation of the Wnt/β-catenin negative regulators ZNRF3 or RNF43. These results indicate that LGR5 is a negative regulator of canonical Wnt signaling in the absence of their cognate ligands (R-spondins) and that high β-catenin/TCF/LEF transcriptional activity does not involve necessarily increase of self-renewal potential in these colorectal cancer cell models studied.; El factor de transcripción SOX2 es una proteína clave implicada en las propiedades adscritas a células madre y también está implicado en la iniciación, mantenimiento y progresión tumoral en distintos tipos de cáncer. Mediante estudio in vitro de las consecuencias fenotípicas de la sobreexpresión y represión de SOX2 en un grupo de líneas celulares, nos hemos centrado en el estudio de dos lineas celulares isogénicas de cáncer colorectal (SW620 y SW480) que presentan una marcada expresión diferencial de SOX2 que correlaciona positivamente con su agresividad. En conjunto, hemos encontrado que altos niveles de SOX2 induce daño al DNA e inducción de especies reactivas de oxígeno, arresto en ciclo celular y apoptosis. También hemos determinado que la represión de SOX2 en la línea metastásica de cáncer colorrectal SW620, induce arresto en G1 y que éste depende parcialmente en los…