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Charles Farrar Browne

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miRNAs, Prostate Cancer and Resistance to Treatment. Role of Metallothionein

Cancer is the leading cause of mortality in Western countries and the second leading cause of death in developing countries [1]. The burden of cancer is rising in economically developing countries: their population is aging and growing and it adopts cancer-associated lifestyle choices including smoking, physical inactivity, and “westernized” diets [2]. Tumour formation has been analysed from all possible aspects (genome, transcriptome, metabolone and other -omes). In this review, we concentrate on two aspects of cancer, namely zinc metabolism and function of miRNAs and on the role of these factors in response to chemotherapy, with special respect to prostate cancer.

Among other characteristics of prostate, healthy and particularly tumorous prostate tissue is unique in its relation to zinc ions. Healthy prostate is a highly specialized in zinc accumulating processes, intracellular zinc level ranges in up to tenfold concentrations compared to most other tissues [3]. In contrast, since the early stages of tumorigenesis a significant decrease of intracellular zinc concentration has been presented in many studies [4-7]. Although some conflicting results were reported [8], the decrease of prostate’ tissue zinc may be considered as well evidenced and established [9]. Due to the fact that zinc can not freely pass through the membranes, the crucial role in the maintenance of intracellular zinc level is provided by zinc-transporting proteins, ZIPs (Zrt- Irt like protein or Zinc Iron permease) and ZnTs (Zinc transporters). Zinc transport has been discussed in detail in several recent reviews [10, 11]; this review emphasises in particular on the decrease of cellular zinc in prostate cancer notably caused by down-regulation of zinc transporter hZIP1 expression [9, 12, 13]. Mechanisms causing the down-regulation of hZIP1 and other transporters in prostate cancer have been addressed recently\. Whereas no mutations were identified in the zinc transporters’ genes [10, 12], the attention was focused on epigenetic processes; association of silenced AP-2alpha and ZIPs has been studied on in situ model [14]. hZIP1 is very likely down-regulated by Ras Responsive Element Binding Protein-1 (RREB-1) which was shown to be up-regulated in prostate cancer due to Ras-Raf-MEK-ERK cascade [15]. Study by Mihelich et al. also reports a possible regulatory role of miRNA on zinc transporters: a miRNA cluster miR-183-96-182 (miR-96 and miR-183 are expressed as a cluster with miR-182) was found overexpressed in prostate tissue [16]. In this study, the overexpression of this cluster was associated with suppression of multiple zinc transporters, including hZIP1.

The reduction of the cellular zinc in prostate cancer is not only a minor consequence of wide myriad of genetic aberrations, but rather an important step in the pathogenesis. It has been experimentally demonstrated, that the loss of zinc accumulation in situ is essential for prostate cancerogenesis [17]. Thus, the complex understanding of the intracellular zinc, respectively hZIP1 regulation, is of high importance with particular application in targeted therapies. Recently, the role of zinc has been extensively studied. Possible impacts of zinc in cancer development include influence on gene transcription, energetic metabolism, cell migration and invasivity, and cell cycle [18-21]. Interestingly, conflicting results were published regarding various tumours. Zinc may promote cancer proliferation in some cancers, while in other types of tumours it exerts an opposite effect. Those carcinogenic/protective effects of zinc(II) seem to be very complex and they manifest in cancer-dependent manner [19]. The impact of zinc on energetic metabolism of prostatic cells is well-established. Zinc has inhibitory effects on mitochondrial enzyme aconitase which catalyses the conversion of citrate to isocitrate and thus enables the utilization of citrate in Krebs cycle. Due to aconitase inhibition, prostate cells cannot fully utilise citrate oxidation [22]. As an opposite, because zinc(II) level is decreased in cancer, the inhibitory effect of zinc(II) on aconitase is abolished, citrate can enter the Krebs cycle, and cancer cells can then become more energy-efficient [3, 23]. One may speculate that this “energetic turnover” may support prostate cancer cells growth.

Zinc is also known to play an important role in induction of apoptosis. Increased intracellular concentration of zinc induces release of cytochrome C which initiates caspase cascade leading to apoptosis [24, 25]. However, the apoptogenic effects of zinc are cell-specific and in other cell types zinc can play a protective role against apoptosis induced by other factors [19, 26]. As a result of disturbances in zinc homeostasis in prostate tumours, several studies reported changes in the serum zinc(II) level in prostate cancer patients. Studies performed by Adaramoye et al. and Goel et al. revealed significantly lower level in patients of all PSA levels [27, 28]. Similar reduction was observed in group of 41 participants using whole blood analysis of zinc(II) level [29]. However, a study on larger set of participants (1,175 US participants) by Park et al. did not observe any difference and no association between serum zinc level and prostate cancer risk in cancer and control group [30]. The disturbances of zinc homeostasis can be reflected in the activity of transcriptional networks through many regulatory proteins containing zinc in their catalytical centre or in their structure. Among notoriously known regulators of gene transcription proteins from the family of zinc-finger transcription factors are present. It is estimated that about 1 % of human genome is coding for zinc-finger proteins which further emphasises their importance for gene expression regulation. Zinc fingers are small structural protein motifs accommodating one or two zinc atoms that help to stabilise protein folding. micro-RNAs (miRNAs) are another factor often connected with tumour development . In this review, we attempt to demonstrate that zinc homeostasis and miRNAs are in prostate carcinoma part of mutually interlinked network where these factors might influence each other. One protein with zinc-finger domains plausible connecting miRNA metabolism with zinc homeostasis is Lin28 homolog B. This protein is overexpressed in hepatocellular carcinoma and ovarian primitive germ cell tumours [31]. Lin28 was found to inhibit the biogenesis of let-7 miRNAs through a special domain that contains motif zinc-knuckle and specifically binds to the terminal loop of pre-let-7 [32]. Similarly, miR-138 was found to regulate the epithelial-mesenchymal transition via direct targeting of zinc finger E-box-binding homeobox 2 in head and neck squamous cell carcinoma and thus promote cancer progression [33]. Conversely, there were also miRNAs identified with the ability to down-regulate the expression of proteins with zinc fingers domains. Using the bioinformatics approach, miR-181a inhibits the expression of large number of zinc fingers proteins by directly targeting their coding sequences [34]. These inhibitory effects might be due to the multiple target sites mostly located in the regions coding for the ZNF C2H2 domain within the ZNF gene [34]. As one of these mechanisms, promyelocytic leukaemia zinc finger (PLZF) was identified as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region [35]. Through this pathway, the progression of melanoma may be controlled. Alongside to zinc fingers, miRNAs may regulate the expression of other zinc-related proteins associated with tumours – matrix metalloproteases. The expression of this large family of zinc endopeptidases is under control of multiple signalling pathways responding to various hormones, cytokines, and growth factors. MMPs are also regulated post-transcriptionally by controlling mRNA stability, protein translation, and recently by miRNAs [36]. For instance, matrix metalloprotease-2 was found to be regulated by miR-21 in a model of myocardial infarction. MiR-21 directly targets PTEN and through this pathway regulates an increase of MMP-2 in infarct area [37]. In this review, we focus on oncogenic and anti-tumour acting miRNAs, on the function of miRNAs in tumour progression, possible role of miRNAs in acquired resistance to anticancer drugs and relationship to zinc metabolism. Finally, diagnostic potential of miRNAs for identification of cancer from a circulating miRNAs is briefly discussed.

Infrastrukturní vybavení pracoviště bylo uskutečněno díky Evropskému sociálnímu fondu projektu NanoBioTECell GA CR P102/11/1068.

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