Abstract
BackgroundMantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin’s lymphoma with variable treatment responses. There is an urgent need to identify novel markers with prognostic and therapeutic value for MCL. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a lncRNA located at pathognomonic translocation site of t (11; 14) of MCL. MALAT1 is known to be overexpressed in solid tumors and hematologic malignancies. However, the pathological role and clinical relevance of MALAT1 in MCL are not completely understood.MethodsWe quantified MALAT1 in MCL samples (40) and CD19+ B cells by quantitative real time polymerase chain reaction (qRT-PCR) and correlated levels with clinical outcome. We silenced MALAT1 in MCL cell lines and analyzed cells in tumorigenic assays and formation of transcription complexes.ResultsWe found that the expression of MALAT1 was elevated in human MCL tumors and cell lines as compared to normal controls, and the elevated levels of MALAT1 correlated with higher MCL international prognostic index (MIPI) and reduced overall survival. MCL with knockdown of MALAT1 showed impaired cell proliferation, facilitated apoptosis and produced fewer clonogenic foci. The increased expression of p21 and p27 upon MALAT1 knockdown was regulated by enhancer of zeste homolog 2 (EZH2). Moreover, decreased phosphorylation of EZH2 at T350 attenuated the binding to MALAT1.ConclusionsOur findings illuminate the oncogenic role of MALAT1, which may serve as a novel biomarker and as a therapeutic target in MCL.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1100-9) contains supplementary material, which is available to authorized users.
Highlights
Mantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin’s lymphoma with variable treatment responses
We found that the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression level were closely associated with MCL international prognostic index (MIPI) (P < 0.05; Fig. 1b), and significantly higher in the high and intermediate risk groups compared to the low Effect of MALAT1 on MCL cell proliferation, apoptosis, and cell cycle progression The basal expression level of MALAT1 was determined in six mantle cell lymphoma derived cell lines (Z-138, Mino, REC-1, Jeko-1, JVM2 and Granta-519) (Additional file 2: Figure S1), the MCL cells with higher expression of MALAT1 (Mino and Jeko-1) which were used for additional experiments
After MALAT1 knockdown, cell proliferation was inhibited and apoptosis rate was increased in MCL cell lines, suggesting that MALAT1 could function as a potential oncogene in MCL
Summary
Mantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin’s lymphoma with variable treatment responses. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. With an annual incidence of 0.5 per 100,000 populations in Western countries, mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma (NHL), comprising about 6% of NHL cases [1]. Despite an initial therapeutic response, patients consistently develop recurrence and chemoresistance [2]. The noncoding transcripts that are more than 200 nucleotides in length are termed long noncoding RNAs (lncRNAs). It has been demonstrated that lncRNAs influence tumor progression through modulating cell cycle, survival, immune response or pluripotency, through their interactions with DNA, protein, and RNA [6, 7]
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