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Title

Vitamin D, VDR and colon cancer

AuthorsMuñoz Terol, Alberto ; Larriba, María Jesús ; Barbáchano, Antonio ; Fernández-Barral, A. ; Ferrer-Mayorga, Gemma ; Costales-Carrera, Alba
Issue Date2015
Citation15th ASEICA International Congress (2015)
AbstractColorectal cancer (CRC) is one of the most frequent and mortal neoplasias worldwide. Despite improvements in CRC patient management and treatment in the last twenty years, no satisfactory therapy exists when surgery is not curative. There is thus a clear need for increased prevention, early diagnosis, novel treatments and better knowledge of this disease. The active vitamin D derivative 1α.25-dihydroxyvitamin D3 (calcitriol or 1,25(OH)2D3) is a pleiotropic hormone that, in addition to its classical effects on the regulation of calcium and phosphate homeostasis and bone biology, modulates proliferation, survival, differentiation and metabolism, and potentiates the antitumoral activity of certain chemotherapeutic agents, in a cell-type- and -context-dependent manner in many ce lis in the organism. These effects rely on the activation of vitamin D receptor (VDR), a member of the superfamily of nuclear receptors that regulares the transcription rate of hundreds of human genes. Many epidemiological studies suggest that vitamin D deficiency is associated with increased colorectal cancer risk and mortality. Additionally, high circulating 1,25(OH)2D3 levels at diagnosis associate with better outcome in CRC. However, definitive clinical evidence of the protective action of vitamin D awaits for the results of ongoing prospective intervention trials. 1,25(OH)2D3 inhibits proliferation and prometes epithelial differentiation of human colon carcinoma ce lis. We have reported that 1,25(OH)2D3 induces the expression of the key intercellular adhesion molecule and invasion suppressor E-cadherin and antagonizes the Wnt/β-catenin signaling pathway, whose alteration initiates and fuels colon tumorigenesis. Moreover, we have reported the regulation by 1,25(OH)2D3 of several genes that variably affect CRC such as SPROUTY(SPRY-2, DICKKOPF(DKK)-1, CST5/Cystatin D or KDM6BIJMJD3. In vivo, 1,25(OH)2D3 reduces intestinal tumorigenesis inApcM> mice and in other mouse models of colon cancer.Aiso,VDR deficiency in mice (Ydr'·) provokes colonic hyperplasia and a strong oxidative stress, and we and others have shown that it in creases tumor load in ApcMin mice. We have also shown that SNAI and SNAI2 genes encoding the epithelial-to-mesenchymal inducers SNAILI and SNAIL2/SLUG repress VDR and that an inverse relation between the expression of these genes exist in human colon tumors. Today it is accepted that both tumor stroma and the alteration of tissue stem cells play crucial roles in cancer. Fibroblasts are the major stromal cellular component and u pon activation by the tumor microenvironment contribute to tumorigenesis. Recendy, we have started the study of the action of 1,25(OH)2D3 on CRC patient-derived normal and cancer-associated fibroblasts and on normal and cancer stem cells.lnitial data of the effects of 1,25(OH)2D3 on these two key tumor compartments will be presented.
DescriptionResumen del trabajo presentado al 15th International Congress of the ASociación Española de Investigación sobre el CAncer (ASEICA), celebrado en Sevilla del 21 al 23 de octubre de 2015.
URIhttp://hdl.handle.net/10261/152774
Appears in Collections:(IIBM) Comunicaciones congresos
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