Long non-coding RNA expression in T and NK cell lymphomas : in relation to polycomb repressive complex pathway

Abstract

Long non-coding RNA (lncRNA) is a non-protein-coding RNA molecule longer than 200 nucleotides functioning in target gene regulation at transcriptional or post-transcriptional level. Recently, tumor type specific expression patterns of lncRNAs have been reported in several types of tumors and thus draw attention to lncRNA as a prognostic marker as well as a therapeutic target. However, the clinicopathologic studies on the expression pattern of lncRNAs in T and NK cell lymphoma have not yet been reported. Thus, the expression pattern of seven lncRNAs (ANRIL, H19, HEIH, HOTAIR, KCNQ1, MALAT1, and TUG1) and their relationship with polycomb repressive complex (PRC) pathway markers (BMI1, EZH2, H3K27me3, and SUZ12) were investigated using 167 clinical samples and 6 lymphoma cell lines. Their role as a prognostic marker was also analyzed. Real-time polymerase chain reaction using RNAs prepared from formalin-fixed paraffin-embedded tissue samples and T and NK cell lymphoma cell lines demonstrated statistically significant high expression of lncRNA MALAT1 in both clinical samples and cell lines. Immunohistochemistry using clinical samples revealed correlation of BMI1 with all other PRC-pathway markers. Multiple linear regression analysis demonstrated independent correlation of BMI1 with H3K27me3 expression and tendency of correlation between lncRNA MALAT1 and BMI expression. RNA immunoprecipitation assay in a HH cell line demonstrated direct binding of lncRNA MALAT1 with EZH2, SUZ12 and H3K27me3. Transfection of si-MALAT1 induced no significant changes of all four PRC pathway markers and significantly decreased biding of lncRNA MALAT1 with EZH2 and SUZ12. Although there was no distinct correlation between lncRNA MALAT1 expression status and clinicopathologic variables, high lncRNA MALAT1 expression demonstrated statistically significant inferior overall survival in cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and T-lymphoblastic lymphoma. High BMI1 expression was also associated with statistically significant inferior overall survival in mature T cell lymphoma and PTCL-NOS, additionally, poor overall survival of marginal significance in extranodal NK/T-cell lymphoma. So lncRNA MALAT1 upregulated in T and NK cell lymphomas and associated with inferior overall survival interacts with PRC2 proteins by direct binding and induce BMI1 activation possibly through histone modification of H3K26. LncRNA MALAT1, like BMI1, could serve as a prognostic marker as well as a therapeutic target in T and NK cell lymphoma.