MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes

Abstract

IntroductionMicroRNAs (miRNAs) are small (20-24 nt's), noncoding RNAs that function as key regulators of gene expression. By pairing with the transcripts of protein-coding genes, they mediate cleavage of the targeted mRNAs or repression of their productive translation. [1][2][3] Notably, miRNAs exhibit dynamic temporal and spatial expression patterns, disruption of which may be associated with tumorigenesis. [4][5][6][7] The C13orf25/miR-17-92 cluster encodes 6 miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92). The miR-17-92 cluster is known to be overexpressed in a variety of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, follicular lymphoma, and mantle cell lymphoma, 5,[8][9][10][11][12][13] all of which arise through various primary and additional genetic changes, including genomic translocations, losses, and amplifications. [8][9][10][11][12][13] Recurrent overexpression of miR-17-92 in B-cell lymphomas suggests the polycistron possesses tumorigenic potential. Consistent with that idea, He et al demonstrated that forced expression of the miR-17-19b-1 (a miR-17-92 variant) in the Eu-myc transgenic mouse model of B-cell lymphoma accelerated disease onset and progression. 5 This suggests dysregulation of the miR-17-92 polycistron contributes to lymphomagenesis by repressing tumor suppressor gene(s). The most likely target of miR-17-92 in lymphomagenesis is the proapoptotic protein Bim, 14 which is known to be a tumor suppressor. 15 Recently, Xiao et al generated a mouse line that selectively overexpressed miR-17-92 in their lymphocytes. 16 As a result, these mice developed lymphoproliferative disease and died prematurely. Following activation, B and T cells from these transgenic mice showed increased proliferation and survival as a result of dysregulation of the proapoptotic gene Bcl2l11/Bim. In addition, Ventura et al established a strain of miR-17-92 knockout mice, 17 which enabled the researchers to demonstrate that the miR-17-92 cluster is essential for the survival signal that mediates progression from the pro-B-to the pre-B-cell stage. The absence of miR-17-92 led to elevated Bim protein levels and inhibition of B-cell development. Finally, Koralov et al ablated Dicer in early B-cell progenitors by conditionally deleting dcr-1 in the B-cell lineage of mice. The resulting phenotype was similar to that seen with miR-17-92 deletion, which was characterized by a developmental block at the transition from the pro-B-to the pre-B-cell stage. The researchers also found that cells lacking Dicer showed increased Bim transcription and Bim protein production. 18 All of these reports suggest that down-regulation of Bim mRNA and protein induced by miR-17-92 overexpression could contribute lymphomagenesis via antiapoptotic activity. Nonetheless, Bim is an unlikely target of miR-17-92 in some aggressive B-cell lymphomas, despite overexpression of the polycistron. For instance, Jeko-1 cells, which are derived from an aggressive B-cell lymphoma, exhibit both homozygous...

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

“…15 Levels of both proteins were increased in cells transfected with the shRNA (Figure 2d), and these were further upregulated by increasing concentrations of doxycycline (Dox) in HEK-293 cells. The inhibitor construct also enhanced Bim and PHLPP2 protein expression in HL-60 and U937 cells (Figure 2e).…”

“…13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Known major activators of the miR-17-92 cluster are transcription factor c-MYC and members of the E2F family, whereas p53 acts as a repressor under hypoxic conditions.…”

Normal and oncogenic roles for microRNAs in the developing brain

“…It is evident that miR-17/92 likely represents a key transcriptional target of SHH signaling in CGNPs of the EGL, as these cells undergo expansion during cerebellar development. Targets of the miR-17/92 cluster such as E2F1, E2F3, Pten, AML1, Bim 40 or the p53 effector CDKN1A/ p21, 46 have been identified in different developing tissues and cancers, including B-cell lymphoma and solid tumors. However, targets for repression have yet to be confirmed in cerebellar precursors.…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…For example, in c-mycoverexpressing Raji cells, miR-17-19b-1 reduces the expression of Bim. In BCL-2-overexpressing SUDHL4 cells, miR-17-19b-1 decreases the expression of CDKN1A/p21 and facilitates the G 1 /S transition [22] . In contrast to the function of miR-17-19b-1 in SUDHL4 cells, miR-17/20a inhibits the G 1 /S transition in breast cancer cells by reducing the expression of cyclin D1 [23] .…”

“…In addition to the positive G 1 /S regulators, negative G 1 /S regulators are also targeted by various miRNAs. The CDK inhibitor p21 is targeted by miR-17-92 and miR106b/93 [22,25] in addition to many other miRNAs [50,51] . The p27 and p57 proteins are regulated by miR-221/222 [52,53] and miR92b [54] .…”