Dysregulation of miRNAs in DLBCL: Causative Factor for Pathogenesis, Diagnosis and Prognosis

Abstract

MicroRNA is a small non-coding RNA (sncRNA) involved in gene silencing and regulating post-transcriptional gene expression. miRNAs play an essential role in the pathogenesis of numerous diseases, including diabetes, cardiovascular diseases, viral diseases and cancer. Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL), arising from different stages of B-cell differentiation whose pathogenesis involves miRNAs. Various viral and non-viral vectors are used as a delivery vehicle for introducing specific miRNA inside the cell. Adenoviruses are linear, double-stranded DNA viruses with 35 kb genome size and are extensively used in gene therapy. Meanwhile, Adeno-associated viruses accommodate up to 4.8 kb foreign genetic material and are favorable for transferring miRNA due to small size of miRNA. The genetic material is integrated into the DNA of the host cell by retroviruses so that only dividing cells are infected and stable expression of miRNA is achieved. Over the years, remarkable progress was made to understand DLBCL biology using advanced genomics and epigenomics technologies enabling oncologists to uncover multiple genetic mutations in DLBCL patients. These genetic mutations are involved in epigenetic modification, ability to escape immunosurveillance, impaired BCL6 and NF-κβ signaling pathways and blocking terminal differentiation. These pathways have since been identified and used as therapeutic targets for the treatment of DLBCL. Recently miRNAs were also identified to act either as oncogenes or tumor suppressors in DLBCL pathology by altering the expression levels of some of the known DLBCL related oncogenes. i.e., miR-155, miR-17-92 and miR-21 act as oncogenes by altering the expression levels of MYC, SHIP and FOXO1, respectively, conversely; miR-34a, mir-144 and miR-181a act as tumor suppressors by altering the expression levels of SIRT1, BCL6 and CARD11, respectively. Hundreds of miRNAs have already been identified as biomarkers in the prognosis and diagnosis of DLBCL because of their significant roles in DLBCL pathogenesis. In conclusion, miRNAs in addition to their role as biomarkers of prognosis and diagnosis could also serve as potential therapeutic targets for treating DLBCL.

miRNome expression analysis in canine diffuse large B-cell lymphoma

“…Myc regulates and activates oncomiR-1 that, in turn, targets and inhibits PTEN ( 110 – 112 ), consequently activating AKT ( 113 , 114 ), as well as attenuates the proapoptotic protein BimL ( 115 , 116 ) or transcription factor E2F ( 117 , 118 ) hence, preventing apoptosis and DNA repair. Strong evidence suggests that the aberrant expression of oncomiR-1 leads to cancer development, including B-cell lymphoma in humans ( 119 – 121 ) and murine models ( 102 , 103 , 122 ). In line with previous studies, we observed the overexpression of miR-19b/20a ( 111 , 123 ), which is known for repressing apoptosis and inducing malignant transformation by activating the mammalian target of the rapamycin (mTOR) pathway ( 124 – 126 ) and by suppressing PTEN ( 123 , 127 , 128 ).…”

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

“…Ma et al [ 322 ] demonstrated that BLIMP1 suppression via EBV-miR-BHRF1-2 plays a potential role in EBV-induced lymphomagenesis. Recently evidence indicates that certain miRs act as oncogenes in DLBCL pathology [ 323 ]. In the following section pivotal DLBCL-related miRs that are also signature miRs of cow’s milk and milk exosomes will be discussed in more detail.…”

A novel β-cyclodextrin-assisted enhancement strategy for portable and sensitive detection of miR-21 in human serum

“…4,5 miR-21 is an oncogenic factor that plays a key role in the development of DLBCL. [6][7][8] Several studies have shown that miR-21 is highly expressed in the tissues and serum of DLBCL patients, thus it has potential as a biomarker in disease diagnosis and screening. In addition, miR-21 is also a potential biomarker for DLBCL subtype classication.…”