Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumorsReportar como inadecuado




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Molecular Cancer

, 3:16

First Online: 18 May 2004Received: 06 May 2004Accepted: 18 May 2004

Abstract

BackgroundMale germ cell tumor GCT is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathways that determine the chemotherapy sensitivity in GCT remain largely unknown.

ResultsWe studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and-or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents.

ConclusionsOur findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-3-16 contains supplementary material, which is available to authorized users.

Sanjay Koul, James M McKiernan contributed equally to this work.

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Autor: Sanjay Koul - James M McKiernan - Gopeshwar Narayan - Jane Houldsworth - Jennifer Bacik - Deborah L Dobrzynski - Adel M 

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







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