Abstract
BackgroundProstate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects men from developed countries. Increased knowledge of the biological mechanisms underlying PCa onset and progression are critical for improved clinical management. MicroRNAs (miRNAs) deregulation is common in human cancers, and understanding how it impacts in PCa is of major importance. MiRNAs are mostly downregulated in cancer, although some are overexpressed, playing a critical role in tumor initiation and progression. We aimed to identify miRNAs overexpressed in PCa and subsequently determine its impact in tumorigenesis.ResultsMicroRNA expression profiling in primary PCa and morphological normal prostate (MNPT) tissues identified 17 miRNAs significantly overexpressed in PCa. Expression of three miRNAs, not previously associated with PCa, was subsequently assessed in large independent sets of primary tumors, in which miR-182 and miR-375 were validated, but not miR-32. Significantly higher expression levels of miR-375 were depicted in patients with higher Gleason score and more advanced pathological stage, as well as with regional lymph nodes metastases. Forced expression of miR-375 in PC-3 cells, which display the lowest miR-375 levels among PCa cell lines, increased apoptosis and reduced invasion ability and cell viability. Intriguingly, in 22Rv1 cells, which displayed the highest miR-375 expression, knockdown experiments also attenuated the malignant phenotype. Gene ontology analysis implicated miR-375 in several key pathways deregulated in PCa, including cell cycle and cell differentiation. Moreover, CCND2 was identified as putative miR-375 target in PCa, confirmed by luciferase assay.ConclusionsA dual role for miR-375 in prostate cancer progression is suggested, highlighting the importance of cellular context on microRNA targeting.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0076-2) contains supplementary material, which is available to authorized users.
Highlights
Prostate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects men from developed countries
Because epigenetic alterations play an important role in prostate carcinogenesis and owing to the relative shortage of validated data on miRNA altered expression in PCa, we aimed to identify and validate miRNAs upregulated in this malignancy
Because a report on miR-182 overexpression in PCa was published during the execution of this study [18], we proceeded with miR-375 for further analysis
Summary
Prostate cancer (PCa), a highly incident and heterogeneous malignancy, mostly affects men from developed countries. MiRNAs are mostly downregulated in cancer, some are overexpressed, playing a critical role in tumor initiation and progression. MiRNAs are globally downregulated, some are notoriously upregulated [11] Such trend has been found in PCa, but most studies limit their analysis to expression array results, based on few tumor samples, and generally lacking subsequent validation in larger and independent datasets [5,12]. This may, at the least partially, explain contradictory results in the literature, making it difficult to establish specific PCa miRNA signatures [13]. Assessing miRNAs differential expression in a robust cohort of patients carrying primary tumors and searching for miRNAs targets are critical to investigate its relevance in PCa initiation and progression
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