Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumorsReportar como inadecuado




Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Clinical Epigenetics

, 6:2

First Online: 09 January 2014Received: 09 August 2013Accepted: 13 December 2013

Abstract

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry IHC to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation-downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.

ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy P = 0.02, and varied inversely with global DNA methylation as assessed by LINE1 methylation r = −0.58, P = 0.006. Tumor RhoA scores increased with decitabine P = 0.03, and RFC1 also increased in patients with pre-decitabine scores ≤150 P = 0.004. Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene alias SLC19A1. SLC19A1 methylation correlated with tumor LINE1 methylation r = 0.45, P = 0.02. There was a small statistically insignificant decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation r = 0.47, P <0.15. While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression r = −0.45, P = 0.19.

ConclusionsIn conclusion, after decitabine administration, there was increased expression of some but not other transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation.

KeywordsDecitabine RhoA RFC1 FOLR1 GLUT4 LINE1 methylation Promoter methylation Electronic supplementary materialThe online version of this article doi:10.1186-1868-7083-6-2 contains supplementary material, which is available to authorized users.

Jean-Pierre Issa, Ignacio I Wistuba and Razelle Kurzrock contributed equally to this work.

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Autor: David J Stewart - Maria I Nunez - Jaroslav Jelinek - David Hong - Sanjay Gupta - Jean-Pierre Issa - Ignacio I Wistuba -

Fuente: https://link.springer.com/







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