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.

Pre‐miR‐27a rs895819 polymorphism and risk of diffuse large B‐cell lymphoma

“…Yuan et al found that miR‐27a functions as an oncogene by targeting SPRY2 and regulates the growth, colony formation and migration of pancreatic cancer cells . In addition, previous study has shown miR‐27a was statistically upregulated in DLBCL compared to normal germinal cells . In our study, we observed that mir‐27a levels were upregulated in DLBCL tissues compared with normal tissues.…”

“…10 In addition, previous study has shown miR-27a was statistically upregulated in DLBCL compared to normal germinal cells. 23 In our study, we observed that mir-27a levels were upregulated in DLBCL tissues compared with normal tissues.…”

A Circulating microRNA Signature Predicts Age-Based Development of Lymphoma

“…Additionally, let-7b has typically been thought to be a tumor suppressor in most cancers, but it has been shown in DLBCL that let-7b is overexpressed [31, 42] and suggests that it may be considered an oncomiR in this cancer subtype. In addition to miR-27a and let-7b, the following miRNAs from the miRNA signature were considered to be tumor suppressors for DLBCL: miR-15a [29, 32, 43, 44], let-7c [20, 23], miR-24 [12], and miR-497 [9, 45]. The following miRNAs were categorized as oncomiRs for DLBCL: miR-10b [44], miR-155 [9, 19, 29, 44], let-7b [31, 42], miR-18a [1, 14, 41, 44], and miR-130a [44, 46].…”

Linear and circular PVT1 in hematological malignancies and immune response: two faces of the same coin

“…Indeed, binding sites for EIF4A3, U2AF65, AGO2, AUF1, DGCR8, FUS, HNRNPC, PTB, TAF15, TDP43, TIA1, TIAL1, LIN28A were predicted on circPVT1, with the first 3 RBPs showing the strongest evidence (https://circinteractome.nia.nih.gov/index.html). Among the micro-RNAs regulated by PVT1, miR-26b, miR-203a, miR-214, miR-424 and miR-497 were reported to be deregulated and play a role in the pathogenesis of lymphoma [103][104][105][106][107][108] and/or MM [68,[109][110][111][112][113] and/or leukemia [114][115][116][117][118][119][120][121]. mir-26b appeared among those showing a significant interaction with the core of PVT1coexpressed transcripts (p ≤ 0.05, mirTarbase, https://amp.…”