Abstract
MicroRNAs (miRNAs) are well known for their ability to regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. In various cancers, miRNAs regulate gene expression by altering the epigenetic status of candidate genes that are implicated in various difficult to treat haematological malignancies such as non-Hodgkin lymphoma by acting as either oncogenes or tumour suppressor genes. Cellular and circulating miRNA biomarkers could also be directly utilised as disease markers for diagnosis and monitoring of non-Hodgkin lymphoma (NHL); however, the role of DNA methylation in miRNA expression regulation in NHL requires further scientific inquiry. In this study, we investigated the methylation levels of CpGs in CpG islands spanning the promoter regions of the miR-17–92 cluster host gene and the TET2 gene and correlated them with the expression levels of TET2 mRNA and miR-92a-3p and miR-92a-5p mature miRNAs in NHL cell lines, tumour samples, and the whole blood gDNA of an NHL case control cohort. Increased expression of both miR-92a-3p and miR-92a-5p and aberrant expression of TET2 was observed in NHL cell lines and tumour tissues, as well as disparate levels of dysfunctional promoter CGI methylation. Both miR-92a and TET2 may play a concerted role in NHL malignancy and disease pathogenesis.
Highlights
Non-Hodgkin Lymphoma (NHL) is a class of cancer that originates in the lymphatic system, caused by an over-proliferation of malignant B-cells
The expression of miR-92a-3p and miR-92a-5p mature miRNAs and TET2 mRNA were assayed by RT-qPCR, and upstream promoter CGI methylation for each gene was assayed by bisulfite pyrosequencing, in 4 biological replicates of non-Hodgkin lymphoma (NHL) cell lines SU-DHL-4, Mino, Raji, and Toledo, and in peripheral blood mononuclear cell (PBMC) of 6 healthy controls (Figure 2). miR-92a-3p expression was increased in Mino cells compared to controls (Figure 2A, p 0.0145) and miR92a-5p expression increased in Mino (p 0.0013), Raji (p 0.0016), and Toledo (p 0.0200) cells compared to controls miR-92a and TET2 in NHL
One tumour sample displayed Reed-Sternberg-like cells during the histological examination, while our studies showed significantly decreased TET2 expression compared to other diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) tumour samples, as well as compared controls considered (Supplementary Figure S1E)
Summary
Non-Hodgkin Lymphoma (NHL) is a class of cancer that originates in the lymphatic system, caused by an over-proliferation of malignant B-cells. Aggressive subtypes account for approximately 60% of cases, and a significant number of NHL patients suffer relapse on various treatments, with refractory NHL having a much poorer prognosis despite access to extensive chemotherapy and immunotherapy regimes (Michot et al, 2018; Sarkozy and Sehn, 2018; Ayers et al, 2020). Overall, this makes NHL an intractable disease to manage and treat, highlighting the need for reliable and subtype-specific diagnostic and prognostic biomarkers
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