Abstract
BackgroundMicroRNAs (miRNAs) are crucial molecules that regulate gene expression and hence pathways that are key to prostate cancer progression. These non-coding RNAs are highly deregulated in prostate cancer thus facilitating progression of the disease. Among the many genes that have gained importance in this disease, Migration and invasion enhancer 1 (MIEN1), a novel gene located next to HER2/neu in the 17q12 amplicon of the human chromosome, has been shown to enhance prostate cancer cell migration and invasion, two key processes in cancer progression. MIEN1 is differentially expressed between normal and cancer cells and tissues. Understanding the regulation of MIEN1 by microRNA may enable development of better targeting strategies.MethodsThe miRNAs that could target MIEN1 were predicted by in silico algorithms and microarray analysis. The validation for miRNA expression was performed by qPCR and northern blotting in cells and by in situ hybridization in tissues. MIEN1 and levels of other molecules upon miRNA regulation was determined by Western blotting, qPCR, and immunofluorescence. The functional effects of miRNA on cells were determined by wound healing cell migration, Boyden chamber cell invasion, clonal and colony formation assays. For knockdown or overexpression of the miRNA or overexpression of MIEN1 3′UTR, cells were transfected with the oligomiRs and plasmids, respectively.ResultsA novel miRNA, hsa-miR-940 (miR-940), identified and validated to be highly expressed in immortalized normal cells compared to cancer cells, is a regulator of MIEN1. Analysis of human prostate tumors and their matched normal tissues confirmed that miR-940 is highly expressed in the normal tissues compared to its low to negligible expression in the tumors. While MIEN1 is a direct target of miR-940, miR-940 alters MIEN1 RNA, in a quantity as well as cell dependent context, along with altering its downstream effectors. The miR-940 inhibited migratory and invasive potential of cells, attenuated their anchorage-independent growth ability, and increased E-cadherin expression, implicating its role in mesenchymal-to-epithelial transition (MET).ConclusionsThese results, for the first time, implicate miR-940, a regulator of MIEN1, as a promising novel diagnostic and prognostic tool for prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-250) contains supplementary material, which is available to authorized users.
Highlights
MicroRNAs are crucial molecules that regulate gene expression and pathways that are key to prostate cancer progression
Though studies have been performed with respect to certain miRNAs and their specific targets in prostate cancer [13,14], not much is known about novel miRNAs targeting the players of cancer progression that can be used as diagnostic markers for early detection, or detection of a possible recurrence or resistance, or therapeutic agents to slow the progression
Migration and invasion enhancer 1 (MIEN1) is post-transcriptionally regulated by microRNAs In various androgen dependent and castration-resistant prostate cancer cells, both MIEN1 Messenger Ribonucleic acid (RNA) (mRNA) and protein are highly expressed compared to the immortalized normal cells of the prostate [15]
Summary
MicroRNAs (miRNAs) are crucial molecules that regulate gene expression and pathways that are key to prostate cancer progression. Though studies have been performed with respect to certain miRNAs and their specific targets in prostate cancer [13,14], not much is known about novel miRNAs targeting the players of cancer progression that can be used as diagnostic markers for early detection, or detection of a possible recurrence or resistance, or therapeutic agents to slow the progression. Identification of these novel miRNAs and their target gene (s), and the pathways they affect during cancer progression, will provide new insights into using them for diagnosis or determination of specific therapy regimens
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