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Article

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

1
Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
2
Dr. Senckenberg Institute of Pathology, Goethe University Frankfurt, D-60590 Frankfurt, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Elisabetta Abruzzese
Cancers 2021, 13(13), 3131; https://doi.org/10.3390/cancers13133131
Received: 14 May 2021 / Revised: 28 May 2021 / Accepted: 14 June 2021 / Published: 23 June 2021
(This article belongs to the Special Issue Hodgkin Lymphoma)
The role of transcriptionally deregulated miRNAs (microRNAs) in classical Hodgkin lymphoma (cHL) is still not fully understood. To address this issue, we have performed global miRNA expression profiling of commonly used cHL cell lines and we present a complete cHL miRNome (microRNome). Within this group, we identify miRNAs recurrently deregulated in cHL cell lines, and compare them to non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells. Moreover, we show that several of the recurrently overexpressed miRNAs in cHL cell lines, and also primary microdissected HRS (Hodgkin and Reed-Sternberg) cells, target known B-cell-related transcription factors and NF-κB inhibitors. These findings provide evidence that deregulated miRNAs contribute to the loss of B-cell phenotype and NF-κB activation observed in this lymphoma.
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. View Full-Text
Keywords: classical Hodgkin lymphoma; microdissection; miRNA; loss of B-cell phenotype; NF-κB; B-cell transcription factors classical Hodgkin lymphoma; microdissection; miRNA; loss of B-cell phenotype; NF-κB; B-cell transcription factors
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MDPI and ACS Style

Paczkowska, J.; Janiszewska, J.; Ustaszewski, A.; Bein, J.; Skalski, M.; Dzikiewicz-Krawczyk, A.; Rozwadowska, N.; Hansmann, M.-L.; Hartmann, S.; Giefing, M. Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma. Cancers 2021, 13, 3131. https://doi.org/10.3390/cancers13133131

AMA Style

Paczkowska J, Janiszewska J, Ustaszewski A, Bein J, Skalski M, Dzikiewicz-Krawczyk A, Rozwadowska N, Hansmann M-L, Hartmann S, Giefing M. Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma. Cancers. 2021; 13(13):3131. https://doi.org/10.3390/cancers13133131

Chicago/Turabian Style

Paczkowska, Julia, Joanna Janiszewska, Adam Ustaszewski, Julia Bein, Marcin Skalski, Agnieszka Dzikiewicz-Krawczyk, Natalia Rozwadowska, Martin-Leo Hansmann, Sylvia Hartmann, and Maciej Giefing. 2021. "Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma" Cancers 13, no. 13: 3131. https://doi.org/10.3390/cancers13133131

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