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Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma

STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by...

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Autores principales: Nagel, Stefan, Meyer, Corinna, Eberth, Sonja, Haake, Josephine, Pommerenke, Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313380/
https://www.ncbi.nlm.nih.gov/pubmed/35884913
http://dx.doi.org/10.3390/biomedicines10071608
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author Nagel, Stefan
Meyer, Corinna
Eberth, Sonja
Haake, Josephine
Pommerenke, Claudia
author_facet Nagel, Stefan
Meyer, Corinna
Eberth, Sonja
Haake, Josephine
Pommerenke, Claudia
author_sort Nagel, Stefan
collection PubMed
description STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, deregulation of developmental transcription factors, and EBV activity. HL cell lines represent useful models to investigate molecular principles and deduced treatment options of this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but, nevertheless, HLX-negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and expression profiling data revealed several amplified and overexpressed gene candidates involved in opposed regulation of STAT3 and EBV. Corresponding knockdown studies demonstrated that IRF4 and NFATC2 inhibited STAT3 expression. MIR155 (activated by STAT3) and SPIB (repressed by HLX) showed reduced and elevated expression levels in AM-HLH, respectively. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.
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spelling pubmed-93133802022-07-26 Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma Nagel, Stefan Meyer, Corinna Eberth, Sonja Haake, Josephine Pommerenke, Claudia Biomedicines Article STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, deregulation of developmental transcription factors, and EBV activity. HL cell lines represent useful models to investigate molecular principles and deduced treatment options of this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but, nevertheless, HLX-negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and expression profiling data revealed several amplified and overexpressed gene candidates involved in opposed regulation of STAT3 and EBV. Corresponding knockdown studies demonstrated that IRF4 and NFATC2 inhibited STAT3 expression. MIR155 (activated by STAT3) and SPIB (repressed by HLX) showed reduced and elevated expression levels in AM-HLH, respectively. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL. MDPI 2022-07-06 /pmc/articles/PMC9313380/ /pubmed/35884913 http://dx.doi.org/10.3390/biomedicines10071608 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nagel, Stefan
Meyer, Corinna
Eberth, Sonja
Haake, Josephine
Pommerenke, Claudia
Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma
title Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma
title_full Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma
title_fullStr Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma
title_full_unstemmed Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma
title_short Downregulation of STAT3 in Epstein-Barr Virus-Positive Hodgkin Lymphoma
title_sort downregulation of stat3 in epstein-barr virus-positive hodgkin lymphoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313380/
https://www.ncbi.nlm.nih.gov/pubmed/35884913
http://dx.doi.org/10.3390/biomedicines10071608
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