Abstract
Diffuse large B-cell lymphoma (DLBCL) is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel prognostic markers and therapeutic targets of DLBCL. Recent studies have shown that long non-coding RNAs (lncRNAs) play an important role in the development of cancer. By using the next generation HiSeq sequencing assay, we determined lncRNAs exhibiting differential expression between DLBCL patients and healthy controls. Then, RT-qPCR was performed for identification in clinical samples and cell materials, and lncRNA PANDA was verified to be down-regulated in DLBCL patients and have considerable diagnostic potential. In addition, decreased serum PANDA level was correlated to poorer clinical outcome and lower overall survival in DLBCL patients. Subsequently, we determined the experimental role of lncRNA PANDA in DLBCL progression. Luciferase reporter assay and chromatin immunoprecipitation assay suggested that lncRNA PANDA was induced by p53 and p53 interacts with the promoter region of PANDA. Cell functional assay further indicated that PANDA functioned as a tumor suppressor gene through the suppression of cell growth by a G0/G1 cell cycle arrest in DLBCL. More importantly, Cignal Signal Transduction Reporter Array and western blot assay showed that lncRNA PANDA inactivated the MAPK/ERK signaling pathway. In conclusion, our integrated approach demonstrates that PANDA in DLBCL confers a tumor suppressive function through inhibiting cell proliferation and silencing MAPK/ERK signaling pathway. Thus, PANDA may be a promising therapeutic target for patients with DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL) occurs most commonly in all subtypes of non-Hodgkin lymphoma (NHL), representing more than one-third of all diagnosed NHL cases and making it the most prevalent form of NHL among adults worldwide [1, 2]
On the basis of the date obtained from Hiseq sequencing, we identified 546 long non-coding RNAs (lncRNAs) that were differently expressed more than 2-fold change
In order to determine why lncRNA PANDA is silenced in DLBCL tissues, we focused on transcription factors that potentially bind to the PANDA promoter
Summary
Diffuse large B-cell lymphoma (DLBCL) occurs most commonly in all subtypes of non-Hodgkin lymphoma (NHL), representing more than one-third of all diagnosed NHL cases and making it the most prevalent form of NHL among adults worldwide [1, 2]. Doxorubicin/vincristine/prednisone (R-CHOP) has been seemed as the standard therapy for the patients with DLBCL, remarkably improves the prognosis [3, 4]. It is important to investigate novel biomarkers involved in DLBCL development. Aberrant expression and mutations of lncRNAs can contribute to tumor development and progression by promoting proliferation, invasion, metastasis, and survival [7, 8]. A recent cross-cancer study by the Chinnaiyan group uncovered thousands of novel lncRNAs [9]. Another study by the Maher group identified a large number of novel lncRNAs in lung cancer [10]
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