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.