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Blood, 8 January 2009, Vol. 113, No. 2, pp. 396-402.
Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-07-163907.
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Submitted July 1, 2008
Accepted September 30, 2008
MicroRNA-17-92 downregulates expression of distinct targets in different B-cell lymphoma subtypes
Mika Inomata, Hiroyuki Tagawa*, Yong-Mei Guo, Yoshihiro Kameoka, Naoto Takahashi, and Kenichi Sawada
Department of Internal medicine III, Akita University School of Medicine, Akita, Japan
* Corresponding author; email: htagawa0279jp{at}yahoo.co.jp.
Aberrant overexpression of the miR-17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 downregulates the pro-apoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR-17-92 into two genetically distinct B-cell lymphoma cell lines: Raji cells, which overexpress c-Myc, and SUDHL4 cells, which overexpress Bcl2. Raji cells transfected with miR-17-19b-1 exhibited downregulated expression Bim and a slight upregulation in Bcl2 expression. On the other hand, SUDHL4 cell transfectants showed aggressive cell growth reflecting facilitated cell cycle progression at the G1-S transition and decreased expression of CDKN1A mRNA and p21 protein (CDKN1A/p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR-20a into Jeko-1 cells led to upregulation of CDKN1A/p21, resulting in decreased cell growth with G1-S arrest. Thus, CDKN1A/p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the miR-17-92 polycistron has distinct targets in different B-cell lymphoma subtypes.
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