title: miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients.
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.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. katharina.troppan@medunigraz.at.
authors.forename: Katharina
authors.initials: K
authors.lastname: Troppan
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. kerstin.wenzl@medunigraz.at.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wenzl
authors.affiliation: Department of Experimental Therapeutics, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mpichler@mdanderson.org.|Division of Oncology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. mpichler@mdanderson.org.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. beata.pursche@klinikum-graz.at.
authors.forename: Beata
authors.initials: B
authors.lastname: Pursche
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. daniela.schwarzenbacher@medunigraz.at.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schwarzenbacher
authors.affiliation: Bioinformatics, Institute for Knowledge Discovery, Graz University of Technology, 8010 Graz, Austria. julia.feichtinger@tugraz.at.|Omics Center Graz, BioTechMed Graz, 8010 Graz, Austria. julia.feichtinger@tugraz.at.
authors.forename: Julia
authors.initials: J
authors.lastname: Feichtinger
authors.affiliation: Bioinformatics, Institute for Knowledge Discovery, Graz University of Technology, 8010 Graz, Austria. gerhard.thallinger@tugraz.at.|Omics Center Graz, BioTechMed Graz, 8010 Graz, Austria. gerhard.thallinger@tugraz.at.
authors.forename: Gerhard G
authors.initials: GG
authors.lastname: Thallinger
authors.affiliation: Department of Pathology, Medical University Graz, 8036 Graz, Austria. christine.beham@medunigraz.at.
authors.forename: Christine
authors.initials: C
authors.lastname: Beham-Schmid
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. peter.neumeister@medunigraz.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Neumeister
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria. alexander.deutsch@medunigraz.at.
authors.forename: Alexander
authors.initials: A
authors.lastname: Deutsch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C559640:MIRN497 microRNA, human; D035683:MicroRNAs; C531408:mirn199 microRNA, human
keywords: DLBCL; chemosensitivity; miRNA-199a; miRNA-497; prognosis