title: Downregulation of telomerase maintenance-relatedACDexpression in patients undergoing immunosuppresive therapy following kidney transplantation.
abstract: Chronic administration of immunosuppressants has been associated with long-term consequences, including a higher risk of neoplasm development. The processes regulating telomere function exert a major influence on human cancer biology. The present study aimed to assess the effect of immunosuppressive therapy on the expression of genes associated with telomere maintenance and protection in patients following renal transplantation. A total of 51 patients that had undergone kidney transplantation and 54 healthy controls were enrolled in the study. The 51 transplant patients received a three-drug immunosuppressive regimen consisting of cyclosporine A, prednisone and mycophenolate mofetil. In stage 1 of the study, the expression profiles of 123 transcripts, which represented 70 genes, were assessed in peripheral mononuclear blood cells using an oligonucleotide microarray technique in 8 transplant recipients and 4 healthy control subjects. Among the analyzed transcripts, the expression levels of 4 differed significantly between the studied groups; however, only theACD(adrenocortical dysplasia homolog) gene, encoding the telomere-binding protein POT1-interacting protein 1 (TPP1), was sufficiently specific for telomere homeostasis. The expression ofACDwas downregulated in transplant recipients (fold change, 2.11; P=0.006). In stage 2 of the study, reverse transcription-quantitative polymerase chain reaction analysis ofACD,DKC1andhTERTmRNA was conducted for all transplant patients and control subjects. The results confirmed the downregulation of the ACD gene in patients that had received immunosuppressive therapy (P=0.002). The results of the present study indicate that the downregulation of ACD gene transcription, and thus TPP1 protein expression, may enhance the capacity for cell immortalization, despite normal levels of other key telomere maintenance factors, in patients undergoing immunosuppressive therapy. Furthermore, the results indicate that TPP1 has potential for use as an early clinical marker and/or therapeutic target for cancer in patients following organ transplantation.
authors.affiliation: Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, 41-800 Zabrze, Silesia, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witkowska
authors.affiliation: Department of Molecular Biology, Medical University of Silesia, 41-200 Sosnowiec, Silesia, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Strzalka-Mrozik
authors.affiliation: Division of Statistics, Medical University of Silesia, 41-200 Sosnowiec, Silesia, Poland.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Owczarek
authors.affiliation: Department of Molecular Biology, Medical University of Silesia, 41-200 Sosnowiec, Silesia, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gola
authors.affiliation: Department of Molecular Biology, Medical University of Silesia, 41-200 Sosnowiec, Silesia, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Mazurek
authors.affiliation: Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, 41-800 Zabrze, Silesia, Poland.
authors.forename: Wladyslaw
authors.initials: W
authors.lastname: Grzeszczak
authors.affiliation: Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, 41-800 Zabrze, Silesia, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Gumprecht
keywords: ACD gene; TPP1; immunosupression; kidney transplantation; telomerase