MiR-17* Suppresses Tumorigenicity of Prostate Cancer by Inhibiting Mitochondrial Antioxidant Enzymes

Yong Xu,Jiayou Zhang,Daret K St Clair,William H St Clair,Fang Fang,Sajni Josson,Andrei L Gartel

doi:10.1371/journal.pone.0014356

Abstract

Aberrant micro RNA (miRNA) expression has been implicated in the pathogenesis of cancer. Recent studies have shown that the miR-17-92 cluster is overexpressed in many types of cancer. The oncogenic function of mature miRNAs encoded by the miR-17–92 cluster has been identified from the 5′ arm of six precursors. However, the function of the miRNAs produced from the 3′ arm of these precursors remains unknown. The present study demonstrates that miR-17* is able to suppress critical primary mitochondrial antioxidant enzymes, such as manganese superoxide dismutase (MnSOD), glutathione peroxidase-2 (GPX2) and thioredoxin reductase-2 (TrxR2). Transfection of miR-17* into prostate cancer PC-3 cells significantly reduces levels of the three antioxidant proteins and activity of the luciferase reporter under the control of miR-17* binding sequences located in the 3′-untranslated regions of the three target genes. Disulfiram (DSF), a dithiolcarbomate drug shown to have an anticancer effect, induces the level of mature miR-17* and cell death in PCa cells, which can be attenuated by transfection of antisense miR-17*. Increasing miR-17* level in PC-3 cells by a Tet-on based conditional expression system markedly suppresses its tumorigencity. These results suggest that miR-17* may suppress tumorigenicity of prostate cancer through inhibition of mitochondrial antioxidant enzymes.

Highlights

Micro RNA,22 nucleotide RNA molecules that generally repress the translation of target messenger RNAs, is involved in various aspects of physiogenesis and pathogenesis [1,2]
The level of miR-17 and the ratio of miR17 to miR-17* in Prostate cancer (PCa) cells were higher than levels in noncancerous cells (Fig. 1A)
By searching miRbase, we found that manganese superoxide dismutase (MnSOD), Gpx2 and thioredoxin reductase-2 (TrxR2), three important mitochondrial antioxidant proteins that are essential for detoxification of O2.2 and H2O2, are potential targets of miR-17*

Summary

Introduction

Micro RNA (miRNA), ,22 nucleotide RNA molecules that generally repress the translation of target messenger RNAs, is involved in various aspects of physiogenesis and pathogenesis [1,2]. The miR-17-92 cluster encodes six miRNAs, including miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92, which are amplified in more types of cancer tissues than in corresponding normal tissues [3,4,5]. The majority of miRNAs identified as having the ability to alter phenotype and development of cancer are generated from the 59 arm of miRNA precursors. Deregulation of redox status is involved in a variety of pathogeneses including cancer. Reactive oxygen species (ROS) generated from oxygen metabolism is detoxified by multiple antioxidant pathways [9]. A consequence of the high metabolism of rapidly growing cancer cells is the rapid generation of cellular ROS. Cancer cells require a high antioxidant defense system to cope with the high levels of ROS production [13,14]. Selective inhibition of antioxidant systems is an option for cancer intervention

Methods

Results

Conclusion