Abstract
PurposeProstate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa.Experimental DesignLevels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts.ResultsWe identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens.ConclusionsThese results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa.
Highlights
Prostate cancer (PCa) is the most commonly occurring malignancy and the second most frequent cause of cancer-related mortality in men in the US
These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa
Let-7c is Expressed in PCa Cells Our previous studies using miRNA microarrays showed that let
Summary
Prostate cancer (PCa) is the most commonly occurring malignancy and the second most frequent cause of cancer-related mortality in men in the US. The majority of patients with advanced PCa respond initially to androgen deprivation therapy, but relapse due to the growth of castration resistant prostate cancer (CRPC) cells. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that can interfere with protein expression either by inducing cleavage of their specific target mRNAs or by inhibiting their translation. Mature miRNAs are evolutionarily conserved ,22nt single stranded RNAs resulting from a multistep processing of larger precursor molecules via Drosha and Dicer. The mature miRNAs are incorporated into the RISC complex along with their target mRNAs which are recognized by sequence complementarity in the 3’-UTR [1]. MiRNAs have been shown to regulate a rapidly increasing list of complex biological processes including differentiation, cell cycle, apoptosis and metabolism [2]. An overwhelming amount of new evidence points to their roles as tumor suppressors or oncogenes which presents a whole spectrum of novel diagnostic and therapeutic opportunities [1,3]
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