MiR-17/106b seed family regulates p21 in Hodgkin's lymphoma

Johan H. Gibcus, Bart-Jan Kroesen, Roelof Koster, Nancy Halsema, Debora de Jong, Steven de Jong, Sibrand Poppema, Joost Kluiver, Arjan Diepstra, Anke van den Berg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)

Abstract

Hodgkin's lymphoma (HL) is a B cell-derived lymphoma characterized by a minority of malignant Hodgkin Reed-Sternberg (HRS) cells that have lost their normal B cell phenotype. Alterations in the cell cycle and apoptosis pathways might contribute to their resistance to apoptosis and sustained cell cycle progression. A key player in both cell cycle arrest and apoptosis is CDKN1A, encoding p21(waf/cip1) (p21). P21 is regulated by p53 and can function as a cell cycle inhibitor when in the nucleus or as an apoptosis inhibitor when localized in the cytoplasm. We observed expression of p53, p21 and p-p21 in a variable number of HRS cells in 24 of 40 cases. Expression of miR-17 and miR-106a was detected in HRS cells of 10 HL cases. MiR-17/106b seed family members, CDKN1A RNA and p21 protein levels were variable in HL cell lines. We showed effective targeting of the CDKN1A 3' UTR by miR-17/106b in HL cell lines in a luciferase reporter assay and up-regulation of p21 protein levels upon anti-miR-17 treatment of KM-H2 cells. Functional studies indicated a p21-mediated G(1) arrest after miR-17/106b down-regulation in KM-H2, whereas no G1 arrest was observed for U-HO1 and L428. This difference could not be explained by differences in the 3' UTR, the cellular location of p21 or expression variation during cell cycle progression. A strong correlation was observed for the miR-17/106b: CDKN1A ratio and the responsiveness to miR-17 inhibition, ie a low ratio in KM-H2 and an extremely high ratio in the two unresponsive HL cell lines. In conclusion, we show that miR-17/106b regulates p21 protein levels in HL and that the effect of miR-17/106b-mediated inhibition depends on the miRNA : target gene ratio. Thus, in HL high miR-17/106b expression contributes to a dysfunctional p53 pathway and thereby also to the malignant phenotype. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Original languageEnglish
Pages (from-to)609-617
Number of pages9
JournalJOURNAL OF PATHOLOGY
Volume225
Issue number4
DOIs
Publication statusPublished - Dec-2011

Keywords

  • Hodgkin's lymphoma
  • p21
  • p53
  • miRNA
  • miR17
  • miR106b
  • cell cycle
  • REED-STERNBERG CELLS
  • DISEASE
  • LINE
  • EXPRESSION
  • P21(CIP1/WAF1)
  • PROGRESSION
  • APOPTOSIS
  • LEUKEMIA
  • PROFILE
  • GENE

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