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Int J Mol Sci. 2015 Aug 5;16(8):18077-95. doi: 10.3390/ijms160818077.

miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients.

Author information

1
Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. katharina.troppan@medunigraz.at.
2
Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. kerstin.wenzl@medunigraz.at.
3
Department of Experimental Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mpichler@mdanderson.org.
4
Division of Oncology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. mpichler@mdanderson.org.
5
Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. beata.pursche@klinikum-graz.at.
6
Division of Oncology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. daniela.schwarzenbacher@medunigraz.at.
7
Bioinformatics, Institute for Knowledge Discovery, Graz University of Technology, 8010 Graz, Austria. julia.feichtinger@tugraz.at.
8
Omics Center Graz, BioTechMed Graz, 8010 Graz, Austria. julia.feichtinger@tugraz.at.
9
Bioinformatics, Institute for Knowledge Discovery, Graz University of Technology, 8010 Graz, Austria. gerhard.thallinger@tugraz.at.
10
Omics Center Graz, BioTechMed Graz, 8010 Graz, Austria. gerhard.thallinger@tugraz.at.
11
Department of Pathology, Medical University Graz, 8036 Graz, Austria. christine.beham@medunigraz.at.
12
Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. peter.neumeister@medunigraz.at.
13
Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. alexander.deutsch@medunigraz.at.

Abstract

Micro-RNAs (miRNAs) are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level. miRNAs are involved in cell development, differentiation, apoptosis, and proliferation. miRNAs can either function as tumor suppressor genes or oncogenes in various important pathways. The expression of specific miRNAs has been identified to correlate with tumor prognosis. For miRNA expression analysis real-time PCR on 81 samples was performed, including 63 diffuse large B-cell lymphoma (DLBCL, 15 of germinal center B-cell like subtype, 17 non germinal center B-cell, 23 transformed, and eight unclassified) and 18 controls, including nine peripheral B-cells, 5 germinal-center B-cells, four lymphadenitis samples, and 4 lymphoma cell lines (RI-1, SUDHL4, Karpas, U2932). Expression levels of a panel of 11 miRNAs that have been previously involved in other types of cancer (miR-15b_2, miR-16_1*, miR-16_2, miR-16_2*, miR-27a, miR-27a*, miR-98-1, miR-103a, miR-185, miR-199a, and miR-497) were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective miRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. Seven miRNAs (miR-16_1*, miR-16_2*, miR-27a, miR-103, miR-185, miR-199, and miR-497) were statistically significantly up-regulated in DLBCL compared to normal germinal cells. However, high expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL.

KEYWORDS:

DLBCL; chemosensitivity; miRNA-199a; miRNA-497; prognosis

PMID:
26251897
PMCID:
PMC4581236
DOI:
10.3390/ijms160818077
[Indexed for MEDLINE]
Free PMC Article
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