MiR-210: an important player in the pathogenesis of preeclampsia?

© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd doi:10.1111/j.1582-4934.2011.01370.x Hypoxia is a common feature in solid neoplastic microenvironment and a well-documented factor attributable to therapeutic failure in clinical oncology. Low oxygen availability also plays a central role in the pathogenesis of major ischaemic disorders, such as acute myocardial infarction, stroke and preeclampsia. Most hypoxic responses impacting cellular behaviour are mediated through hypoxia inducible transcription factors (HIFs), composed of alpha (HIF) and beta (HIF) subunits. For this reason, studies about signalling pathways involved in hypoxic response are mainly concentrated on HIF and its target molecules. Recently, a new class of hypoxia-induced molecules, named hypoxia inducible microRNA (hypoxamirs), is receiving increased attention [1]. Among these miRNAs, miR-210 is unique in that it is robustly and ubiquitously induced by hypoxia in a variety of cell types studied. Several studies have demonstrated the up-regulation of miR-210 in patients with preeclampsia. However, the role of miR-210 in the pathogenesis of the disease is largely unknown. In this issue of the Journal of Cellular and Molecular Medicine, Zhang et al. [2] demonstrate that hypoxia inducible miR-210, regulated by transcriptional factor HIF-1 as well as NFB, plays an important role in the molecular mechanism of preeclampsia. MiR-210 is frequently elevated in primary solid tumours, including head and neck cancer, glioma, melanoma, clear cell renal cell carcinoma and lung, pancreatic and breast cancer [3]. From diagnostic standpoints, it has been found that miR-210 is significantly up-regulated in serum from patients with diffuse large B-cell lymphoma and in plasma of pancreatic cancer patients. In benign disease associated with hypoxia, such as arteriosclerosis obliterans, increased serum levels of miR-210 have also been detected [4]. In recent years, it has been found that miR-210 levels are dramatically increased in the placental tissue derived from patients with preeclampsia. In this issue, Zhang et al. [2] found that miR-210 levels in plasma from preeclampsia patients were significantly higher than those in gestational healthy controls. Furthermore, the expression levels of miR-210 seemed to correlate well with disease severity, suggesting a potential role of circulating miR-210 as novel biomarker for the diagnosis of preeclampsia. However, because of relative small number of patients enrolled, further study in a large scale would be warranted to validate this finding. To verify that the high level of miR-210 could be derived from placental tissues, using cytotrophoblast cells and trophoblast-derived human cells as in vitro model, the authors demonstrated that miR-210 was induced by hypoxia in these cell lines. It has been demonstrated that miR-210 is clearly involved in diverse biological processes such as differentiation, cell cycle, cell survival and tumour progression [3]. However, depending upon different cellular context, some functions of miR-210 maybe significantly vary. To investigate the role in the pathogenesis of preeclampsia, Zhang et al. [2] cultured the cytotrophoblast cells in normoxia and hypoxia, respectively. Transwell assays showed that ectopic expression of miR-210 inhibited the capability of trophoblast cell migration and invasion in normoxia, with hypoxia treatment yielding the similar results. Furthermore, in hypoxia, blocking miR-210 expression with anti-miR-210 could reverse the inhibitory effects of hypoxia. These findings suggest that hypoxia may inhibit migration and invasion of the cytotrophoblast cells by inducing miR-210 expression. Recently, Fasanaro et al. reported that hypoxia and miR-210 stimulated endothelial cell migration [5]. The discrepancy is not difficult to understand, because in different tissue and cellular context, miR-210 may inactivate different targets genes, which may have opposite functions. Up to date, at least more than 35 unique transcripts have been identified and validated as direct targets of miR-210. To elucidate the mechanisms involved in inhibitory effects of miR-210 on cell migration and invasion, the authors concentrated on two transcripts which are putative target genes predicated by computational programs: ephrin-A3 (EFNA3) and homeobox-A9 (HOXA9). The predication was confirmed by 3 -UTR luciferase assay. Realtime quantitative RT-PCR and Western blot analysis demonstrated that the expression of EFNA3 and HOXA9 were inhibited through mechanisms involving mRNA degradation or translational repression. The in vivo expression profile of EFNA3 and HOXA9 was also Commentary