MicroRNA-155-5p Overexpression in Peripheral Blood Mononuclear Cells of Chronic Lymphocytic Leukemia Patients Is a Novel, Independent Molecular Biomarker of Poor Prognosis

Abstract

MicroRNA-155-5p (miR-155-5p) is a proinflammatory, oncogenic miRNA, involved in various physiological processes, including hematopoiesis, immunity, inflammation, and cell lineage differentiation. It regulates important transcription factors, such as E2F2, hypoxia-inducible factor 1 (HIF1), and FOXO3. Recently, the dysregulation of miR-155-5p expression has been linked to chronic lymphocytic leukemia (CLL) pathogenesis. In this research study, we investigated the potential diagnostic and prognostic value of miR-155-5p in CLL. To achieve our goal, we isolated total RNA from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients and 36 nonleukemic blood donors and performed polyadenylation of total RNA and reverse transcription. Next, we quantified miR-155-5p levels using an in-house-developed real-time quantitative PCR method, before proceeding to extensive biostatistical analysis. Thus, it appears that miR-155-5p is significantly overexpressed in PBMCs of CLL patients and can distinguish them from nonleukemic population. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-155-5p expression predicts inferior OS for CLL patients (p < 0.001). Interestingly, miR-155-5p overexpression retains its unfavorable prognostic role in CLL patients stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable region (IGHV)]. Thus, miR-155-5p appears as a promising, independent molecular biomarker of unfavorable prognosis in CLL.

Alternative Splicing Detection Tool—a novel PERL algorithm for sensitive detection of splicing events, based on next-generation sequencing data analysis

“…As microRNAs (miRNAs) bind 3'-UTRs to downregulate the levels of the respective proteins or protein isoforms, alterations in their sequence due to alternative splicing may account for the regulation of splice variants by distinct miRNAs (57). Thus, miRNAs regulating the expression of protein-coding transcripts subjected to intense alternative splicing may constitute very promising molecular biomarkers; such miRNAs include members of the miR-17/92 cluster (58) and its paralogue miR-106a/363, such as miR-92a-3p and miR-20b-5p as well as miR-155-5p, which have pivotal roles in other B-cell malignancies, including chronic lymphocytic leukemia (59)(60)(61). Other such important biomarkers regulating splice variants of protein-coding genes and being clinically significant include miR-15a-5p, miR-16 miR-34a, and miR-96 regulating BCL2 expression (62-65), miR-182 regulating BCL2L12 expression (66), miR-200 family members (67), as well as several other miRNAs (68)(69)(70)(71).…”

Non-coding RNAs: the riddle of the transcriptome and their perspectives in cancer

“…Furthermore, E2F transcription factor 1 (E2F1) is negatively regulated by miR-17/92, provoking attenuated E2F-induced apoptosis and simultaneously contributing to proliferative signal by promoting E2F transcription factor 3 (E2F3) expression (35). Members of the miR-17/92 cluster and its paralogue miR-106a/363, such as miR-92a-3p and miR-20b-5p, along with miR-155-5p have pivotal roles in other B-cell malignancies, including chronic lymphocytic leukemia (36)(37)(38). In particular, miR-155-5p regulates important transcription factors, such as E2F2 and hypoxiainducible factor 1 (HIF1) in leukemic cells (39,40).…”

Evaluation of miR-155 Expression in Cystic Fibrosis Patients

“…The inflammatory RNA binding proteins, including KSRP and TTP, regulate the biogenesis of miR-155 in CF lung epithelial cells (21). This miRNA regulates several genes encoding immunomodulatory, tumor-suppressor, and in[U+FB02]ammatory-related proteins, and its high expression levels are often associated with disorders such as cardiovascular diseases, in[U+FB02]ammation, in[U+FB02]ammatory bowel disease (IBD), and different types of cancer such as colorectal cancer (CRC) (20,(22)(23)(24). miR-155 is upregulated in cancers of B-cell origin (25).…”