Frequent downregulation of BTB and CNC homology 2 expression in Epstein–Barr virus-positive diffuse large B-cell lymphoma

Mai Noujima-Harada, Katsuyoshi Takata, Tomoko Miyata-Takata, Hiroaki Sakurai, Kazuhiko Igarashi, Etsuro Ito, Keina Nagakita, Kohei Taniguchi, Nobuhiko Ohnishi, Shizuma Omote, Tetsuya Tabata, Yasuharu Sato, Tadashi Yoshino

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Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma subtype, and the Epstein–Barr virus (EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 (BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases (P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 (EBV-negative) and FL-18-EB cells (FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18-EB cells, downregulation of phosphorylated transforming growth factor-β-activated kinase 1 (pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18-EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL (P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation.

Original languageEnglish
Pages (from-to)1071-1079
Number of pages9
JournalCancer Science
Volume108
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • BACH2
  • Epstein–Barr virus
  • NFκB
  • TAK1
  • diffuse large B-cell lymphoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Noujima-Harada, M., Takata, K., Miyata-Takata, T., Sakurai, H., Igarashi, K., Ito, E., Nagakita, K., Taniguchi, K., Ohnishi, N., Omote, S., Tabata, T., Sato, Y., & Yoshino, T. (2017). Frequent downregulation of BTB and CNC homology 2 expression in Epstein–Barr virus-positive diffuse large B-cell lymphoma. Cancer Science, 108(5), 1071-1079. https://doi.org/10.1111/cas.13213