Abstract
BackgroundThe mechanism for inactivation of positive regulatory domain containing I (PRDM1), a newly identified tumour suppressor gene in extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT) has not been well defined. The aim of the present study was to investigate the expression of PRDM1 in EN-NK/T-NT and analyse its downregulation by miRNAs.MethodsPRDM1 and miRNA expression were evaluated in EN-NK/T-NT samples by immunohistochemical analysis, qRT-PCR, and in situ hybridisation. Luciferase assays were performed to verify the direct binding of miR-223 to the 3′-untranslated region of PRDM1 mRNA. In addition, the effect of miR-223 on PRDM1 expression was assessed in NK/T lymphoma cell lines by transfecting a miR-223 mimic or inhibitor to increase or decrease the effective expression of miR-223. Overall survival and failure-free survival in EN-NK/T-NT patients were analysed using Kaplan-Meier single-factor analysis and the log-rank test.ResultsInvestigation of the downregulation of PRDM1 in EN-NK/T-NT cases revealed that PRDM1-positive staining might be a favourable predictor of overall survival and failure-free survival in EN-NK/T-NT patients. However, the negative staining of PRDM1 usually presented transcripts, suggesting a possible post-transcriptional regulation. miR-223 and its putative target gene, PRDM1, exhibited opposite patterns of expression in EN-NK/T-NT tissues and cell lines. Moreover, PRDM1 was identified as a direct target gene of miR-223 by luciferase assays. The ectopic expression of miR-223 led to the downregulation of the PRDM1 protein in the NK/T-cell lymphoma cell line, whereas a decrease in miR-223 restored the level of PRDM1 protein.ConclusionsOur findings reveal that the downregulation of the tumour suppressor PRDM1 in EN-NK/T-NT samples is mediated by miR-223 and that PRDM1-positive staining might have prognostic value for evaluating the clinical outcome of EN-NK/T-NT patients.
Highlights
The mechanism for inactivation of positive regulatory domain containing I (PRDM1), a newly identified tumour suppressor gene in extranodal natural killer (NK)/T-cell lymphoma, nasal type (EN-NK/T-NT) has not been well defined
Evaluation of Positive regulatory domain containing I (PRDM1) expression in EN-NK/T-NT samples by IHC The expression of PRDM1 protein in 61 primary ENNK/T-NT tumour specimens was assessed by IHC
The expression of PRDM1 was negative in the majority of EN-NK/T-NT samples (46/61, 75.41%) (Figure 1C), and the remaining EN-NK/T-NT cases (15/61, 24.59%) showed only weak staining (10%-50% positive cells) for PRDM1 (Figure 1A, B); no EN-NK/T-NT samples were strongly positive for PRDM1
Summary
The mechanism for inactivation of positive regulatory domain containing I (PRDM1), a newly identified tumour suppressor gene in extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT) has not been well defined. The aim of the present study was to investigate the expression of PRDM1 in EN-NK/T-NT and analyse its downregulation by miRNAs. Extranodal NK/T-cell lymphoma, nasal type (EN-NK/T-NT) is a major type of natural killer (NK) cell neoplasm, and its incidence is higher in Asia than it is in Western countries [1]. In our recent subtype distribution analysis of 142 Northern Chinese patients with peripheral NK/T cell lymphomas, EN-NK/T-NT was the most prevalent subtype (38.0%) [2]. This tumour usually presents with highly aggressive clinical progression, but the prognosis is variable and depends strongly on clinical factors. The overexpression of transcription factors and aberrant microRNAs (miRNAs) has been associated with tumour oncogenesis [5,6,7]
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