Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

Abstract

A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.

M7G-related miRNA biomarkers for predicting overall survival outcomes for colon carcinoma

“…Yang et.al [33] demonstrated that Hsa-miR-9-5p can be a useful biomarker through bioinformatic analysis of CRC miRNA data. Hsa − miR − 9−5p overexpression induces NF-κB channel activation and inhibits B cell transcription factors to promote Hodgkin lymphoma progression [34]. Jiang et.al claims [35] that miRNA-378d regulates polyadenylation factor dysregulation and causes structural changes in APA that lead to the occurrence of CRC.…”

Identification of two unannotated miRNAs in classic Hodgkin lymphoma cell lines

“…The L-428, KM-H2, L-1236, L-540 cHL cell lines were obtained from collaborating partners and together with HEK-293 cell line were STR typed to confirm their identity. Furthermore, the HEK-293 cell line was used for the transfection experiments in functional analysis [9]. Respective cell culture conditions were described previously [25].…”

“…The BAM files from miRNA-seq of seven cHL cell lines and 10 NHL cell lines [9] were reanalysed in order to detect unannotated RNA-like sequences as potential miRNA candidates. For…”

“…By now, the role of several oncomiRs and tumor suppressor miRNAs was described in cHL [5][6][7]. These include the deregulated miR-155 and miR-196a and miR-23a-3p, which are assumed to contribute to the constitutive NFκB hyperactivation, a process crucial in cHL pathogenesis [6,8,9]. Moreover, also other miRNAs deregulated in cHL such as miR-9, miR-138, miR-150 were described as candidates involved in processes responsible for Hodgkin lymphomagenesis such as immune evasion and impaired B-cell receptor signalling [9].…”

“…In our recent study we have performed high throughput screening of miRNA expression in 7 widely used cHL cell lines and ten non-Hodgkin lymphoma cell lines (NHL) by RNA-seq [9]. Here we mined this dataset with the aim to find miRNAs expressed in cHL and not yet reported in miRBase (release 22.1).…”