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XXII Foro dos Recursos Mariños e da Acuicultura das Rías Galegas, O Grove, 10-11 de outubro de 2019

XVII Congreso Nacional de Acuicultura, Cartagena 7-10 de mayo de 2019

Resumen del trabajo presentado al V Encuentro Científico de Jóvenes Investigadores de la Red Temática de Investigación Cooperativa en Cáncer, celebrado en Pamplona, Navarrra el 5 de octubre de 2015., SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Previously we reported that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1o,25-dihydroxyvitamin D3 through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1o,25-dihydroxyvitamin D3 -induced E-cadherin expression (Barbáchano et al., Oncogene, 2010). Later we found that in human colon cancer cells SPRY2 expression is induced by betacatenin in cooperation with the transcription factor FOX03a instead of TCF/LEF1 proteins. Importantly, the amount of SPRY2 protein correlates with shorter overall survival of colon cancer patients (Ordóñez-Morán et al., Oncogene, 2014). Global transcriptomic analyses show that SPRY2 dysregulates tight junctions, and epithelial polarity genes. A key action of SPRY2 is the upregulation of the major EMT inducer ZEBl, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEBl in human colon tumors. Our data show that ZEBl upregulation by SPRY2 results from the combined induction of ETSl transcription factor and the repression of miR-150 and miR-200 family that target ZEBl RNA. Moreover, SPRY2 increases AKT activation and the blockade of AKT inhibits SPRY2 action. Altogether, our results show a tumorigenic role of SPRY2 in colon cancer that is based on the induction of epithelial-tomesenchymal transition via upregulation of ZEBl.

Trabajo presentado en la IV International Meeting on Marine Research (IMMR 2014), celebrada en Peniche (Portugal) el 10 y 11 de julio de 2014.

Resumen del trabajo presentado al "6th International EMT Meeting: Symposium VI. Cancer and EMT I" celebrado en Alicante (España) del 13 al 16 de noviembre de 2013., The active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1,25(OH)2D3) is a pleiotropic secosteroid hormone with wide regulatory actions. 1,25(OH)2D3 acts via the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors, which binds specific DNA sequences in its target genes and modulates their transcription rate. Additionally, 1,25(OH)2D3 activates rapid, non-genomic signaling pathways. We have reported that 1,25(OH)2D3 inhibits proliferation and induces differentiation of human colon carcinoma cells via the control of a high number of genes and the antagonism of the Wnt/beta-catenin pathway (Pálmer et al., J. Cell Biol., 2001; Cancer Res., 2003). 1,25(OH)2D3 increases the expression of CDH1/E-cadherin RNA and protein through the activation of a rapid non-genomic pathway (Ca2+-RhoA-ROCK-MSK1) and the subsequent increase in transcription (Ordóñez-Morán et al., J. Cell Biol., 2008). Additionally, it induces other proteins involved in epithelial adhesion structures such as the tight junctions components claudin-7, occludin and ZO-1. These effects are partially mediated by the induction of CST5/cystatin D, a protease inhibitor that regulates gene expression within the cell nucleus, and KDM6B/JMJD3 histone H3 lysine 27 demethylase, and by the repression of SPROUTY-2, a modulator of tyrosine kinase receptor signalling (Alvarez-Díaz et al., J. Clin. Invest., 2009; Barbáchano et al., Oncogene, 2010; Pereira et al., Human Mol. Genet., 2011). In addition, CST5/cystatin D and KDM6B/JMJD3 downregulate SNAI1, SNAI2, ZEB1 and ZEB2 genes. Moreover, SPROUTY-2 represses miR-200b/c leading to ZEB1 upregulation, and also several adhesion and polarity genes and ESRP1, an inhibitor of EMT. Remarkably, a reciprocal inhibitory loop exists between 1,25(OH)2D3 and EMT, as SNAIL1 and SNAIL2/SLUG repress VDR expression (Pálmer et al., Nat. Med., 2004; Larriba et al., Carcinogenesis, 2009). Altogether, our results show that 1,25(OH)2D3 represses EMT in human colon carcinoma cells through several mechanisms that affect the expression of EMT regulators and of epithelial adhesion and polarity genes. Conversely, the EMT inducers SNAIL1/2 inactivate the vitamin D system via VDR downregulation.

Resumen del póster presentado al XXXVI Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Madrid del 3 al 6 de septiembre de 2013.-- et al., SPROUTY-2 (SPRY2) is a modulator of receptor tyrosine kinase signalling, and therefore of cell growth and differentiation, with cell type-dependent tumor promoting or suppressive effects. Previously we reported that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1alpha, 25-dihydroxyvitamin D3 through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1alpha, 25-dihydroxyvitamin D3-induced E-cadherin expression. Recent data indicate that in human colon cancer cells SPRY2 expression is induced by beta-catenin in cooperation with the transcription factor FOXO3a instead of TCF/LEF1 proteins. In colon cancer patients, SPRY2 is upregulated in undifferentiated high grade tumors and at the invasive front of low grade carcinomas, and SPRY2 protein expression correlates with nuclear beta-catenin and FOXO3a colocalization. Importantly, the amount of SPRY2 protein correlates with shorter overall survival of colon cancer patients. We have found that SPRY2 dysregulates tight junction and epithelial polarity genes via microRNA-200-dependent upregulation of the transcriptional repressor ZEB1, which provides a mechanistic basis for the tumorigenic role of SPRY2 in colon cancer. In conclusion, our data reveal SPRY2 as a novel Wnt/beta-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer.

Resumen del trabajo presentado al XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Barcelona del 5 al 8 de septiembre de 2011.-- et al., Accumulated evidences indicate that most solid tumors are not homogeneous but built of cancer cell populations with divers biological properties. They follow a hierarchical organization in which self-renewing cancer stem cells (CSC) are in the apex of a differentiation process within the cancerous tissue. CSC can also compose the small reservoir of drug-resistant cells responsible for tumor relapse or can give rise to metastasis. Our laboratory is exploring such heterogeneity and describing novel populations of cancer cells within colon carcinomas responsible for drugresistance, relapse or metastasis, all clinical determinants of patients' survival. Blocking signaling pathways that drive CSC distinctive properties is a new strategy being recently explored in clinical oncology by the use of novel targetdirected drugs. Wnt/β-catenin and PI3K/AKT are two of these pathways playing a central role in CSC homeostasis. We have described the function of their corresponding effectors - β-catenin and FOXO3a - cooperating in colon cancer. Their activation promotes cell scatteringand metastasis regulating a set of common target genes. Unexpectedly, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis from cells with high nuclear β-catenin. β-catenin confers resistance to FOXO3a-induced apoptosis promoted by PI3K and AKT inhibitors in patient-derived cells enriched in CSC, that is reverted by Wnt/β-catenin inhibitor XAV-939. Our findings could have a serious impact on therapy since we demonstrate that nuclear β-catenin heterogeneity compromises the response of different cancer cell populations to anti-tumoral drugs currently in clinical trials and directed against PI3K/AKT oncogenic signal.