Epigenetic inactivation of the hsa-miR-203 in haematological malignancies

Abstract

AbstractmiR-203 is a tumour suppressor microRNA (miRNA). We studied the methylation of hsa-miR-203 in 150 samples including acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL) and non-Hodgkin’s lymphoma (NHL) by methylation-specific PCR, and miRNA expression by stem-loop RT-qPCR. hsa-miR-203 promoter was unmethylated in normal controls but homozygously methylated in two AML and four lymphoma cell lines, in which 5-Aza-2′-deoxycytidine treatment led to promoter demethylation and miR-203 re-expression. Restoration of miR-203 expression in lymphoma cells inhibited cellular proliferation and increased cell death, suggesting an inherent tumour suppressor activity. In primary samples, hsa-miR-203 methylation was absent in CML but detected in 5.0% ALL, 10.0% AML, 42.0% CLL and 38.8% of NHL (including six [60.0%] natural killer-cell, nine [40.9%] B-cell and four [23.5%] T cell NHL). Moreover, hsa-miR-203 methylation was associated with hypermethylation of hsa-miR-34a, -124a and -196b in NHL but not CLL. In CLL, hsa-miR-203 methylation was associated with a higher presenting Hb level (P = 0.033). The projected 10 year overall survival of the CLL patients was 58.2%, which was impacted by Rai stage and high-risk karyotypes but not hsa-miR-203 methylation. hsa-miR-203 was more frequently methylated in lymphoid than myeloid malignancies (P = 0.002). In conclusion, miR-203, a tumour suppressor gene, was hypermethylated in a tumour-specific manner with gene silencing. hsa-miR-203 was more frequently hypermethylated in lymphoid than myeloid malignancies. In NHL, hsa-miR-203 methylation was associated with concomitant methylation of other tumour suppressor miRNAs. The frequent hsa-miR-203 methylation in lymphoid malignancies suggested a pathogenetic role of hsa-miR-203 methylation.

Epidermal growth factor-induced C/EBPbeta participates in EMT by dampening miR-203 in esophageal squamous cell carcinoma

“…Downregulation of miR-203 has been reported in a number of different cancers including ESCC (Castilla et al, 2011;Chen et al, 2011;Chiang et al, 2011;Chim et al, 2011;Feber et al, 2008). The loss of function caused by miR-203 dysregulation is involved in more aggressive tumor behaviors.…”

Mechanisms of epigenetic deregulation in lymphoid neoplasms

“…106 DNA hypermethylation led to miR-124 and miR-203 silencing in several lymphoid malignancies, providing a basis for therapeutic targeting with demethylating agents. [107][108][109][110][111][112] Moreover, genome-wide miRNA profiling studies in ALL further revealed an EZH2 targeted and aberrantly methylated miRNA signature, suggesting that these cases might benefit from EZH2 inhibition. [107][108][109][110][111]113 Along the same lines, miR-26a and miR-29 are repressed by MYC during lymphomagenesis.…”

“…[107][108][109][110][111][112] Moreover, genome-wide miRNA profiling studies in ALL further revealed an EZH2 targeted and aberrantly methylated miRNA signature, suggesting that these cases might benefit from EZH2 inhibition. [107][108][109][110][111]113 Along the same lines, miR-26a and miR-29 are repressed by MYC during lymphomagenesis. 114,115 EZH2 targeting by miR-26a might lead to global deregulation of gene expression, whereas MYC recruits HDAC3 and EZH2 complexes to aberrantly repress miR-29.…”

Epigenetic regulation of miRNA genes in acute leukemia

“…89 Both ABL1 and the BCR -ABL1 fusion gene are relevant targets for the miRNA hsa-miR-203. 90 Hsa-miR-203 is aberrantly methylated in ALL, 72,91 suggesting that silencing of this miRNA may provide a proliferate advantage in BCR-ABL1-positive leukemia or in leukemia with higher levels of ABL1 and that restoration of its expression can be a useful treatment for these patients.…”