The proto-oncogene Pim-1 is a target of miR-33a

Abstract

The constitutively active serine/threonine kinase Pim-1 is upregulated in different cancer types, mainly based on the action of several interleukines and growth factors at the transcriptional level. So far, a regulation of oncogenic Pim-1 by microRNAs (miRNAs) has not been reported. Here, we newly establish miR-33a as a miRNA with potential tumor suppressor activity, acting through inhibition of Pim-1. A screen for miRNA expression in K562 lymphoma, LS174T colon carcinoma and several other cell lines revealed generally low endogenous miR33a levels relative to other miRNAs. Transfection of K562 and LS174T cells with a miR-33a mimic reduced Pim-1 levels substantially. In contrast, the cell-cycle regulator cyclin-dependent kinase 6 predicted to be a conserved miR-33a target, was not downregulated by the miR-33a mimic. Seed mutagenesis of the Pim-1 3 0 -untranslated region in a luciferase reporter construct and in a Pim-1 cDNA expressed in Pim-1-deficient Skov-3 cells demonstrated specific and direct downregulation of Pim-1 by the miR-33a mimic. The persistence of this effect was comparable to that of a small interfering RNA-mediated knockdown of Pim-1, resulting in decelerated cell proliferation. In conclusion, we demonstrate the potential of miR-33a to act as a tumor suppressor miRNA, which suggests miR-33a replacement therapy through delivery of miR mimics as a novel therapeutic strategy.

Mir-33 regulates cell proliferation and cell cycle progression

“…On the other hand, Thomas M et al have recently shown that miR-33 also targets the serine/threonine-protein kinase Pim-1 and inhibits proliferation in K562 and LS174T cells. 36 In addition to miR-33, many miRNAs have been shown to play a role in regulating proliferation and cell cycle progression. 37 The mir-15a-16-1 cluster may induce cell cycle arrest at the G 1 phase by targeting critical cell cycle regulators such as CDK1, CDK2 and CDK6 as well as cyclins (D1, D3 and E1).…”

Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia

“…Luciferase assays with the Pim1 39-UTR found no decrease by miR-124a ( Figure 4H). microRNAs miR-33a (a known Pim1 target) 21 and miR-214 (a putative high-seed match to the Pim1 39UTR), both targeted Pim1 ( Figure 4H). Although the effects of miR-33a were previously reported, this is the first report demonstrating that miR-214 can directly target the Pim1 39UTR.…”

MicroRNA-33a downregulation is associated with tumorigenesis and poor prognosis in patients with hepatocellular carcinoma

“…miR-33a has also been implicated as a tumor suppressor miRNA; Kuo et al (19) identified that miR-33a is downregulated in lung cancer cells and inhibits osteolytic bone metastasis by targeting parathyroid hormone. miR-33a has also been demonstrated Departments of 1 Nuclear Medicine and 2 to act as a tumor suppressor miRNA, and may downregulate the expression of the oncogenic kinase Pim-1 in K562 lymphoma cells and colon carcinoma (20,21). However, the role of miR-33a in HCC is not yet fully characterized.…”