MicroRNAmediated regulation of PCSCs

For the identification of novel PC therapeutic targets it is important to evaluate functional genes that are related with CSCs self-renewal and survival abilities. The experiences with PC therapy showed that PC recurs frequently; meaning that chemotherapy, radiotherapy, androgen-ablation therapy, and radical prostatectomy are not sufficient enough to eliminate TICs or metastatic cells. PCSCs are androgen independent and therapy resistant cells. Thus, generating novel therapies that specifically target PCSCs may be more effective than those that target differentiated PC cells. New approaches depend on CSC exterminating rather than total tumor decay. The limitation for these studies is to be able to specifically target CSCs in normal tissue that also contains its specific SCs; since, they have similar expression-al and antigenic profiles [101]. Consequently, new markers are needed to distinguish CSCs from tissue specific SCs. microRNAs (miRNA) can be considered as such novel therapeutic target molecules for distinguishing PCSCs from normal SCs. MicroRNAs are 21- to 25-nu-cleotide (nt)-long, noncoding RNAs that induce the target mRNA degradation or repress mRNA translation by imperfect binding to their 3'-untranslated region (UTR) [102].

Depending on their expressional profiles and their target-mRNA types miRNAs can be divided into two classes: one that act like oncogenes (oncomiRs) and the other that act like tumor suppressor genes. OncomiRs are commonly up-regulated in tumors and target tumor suppressor mRNA transcripts, causing a decrease of tumor suppressor protein syntheses and thus function. Tumor suppressor miRNAs on the other hand are mostly down-regulated in tumors and therefore cannot target and inhibit the syntheses of the specific oncogene mRNA transcripts into oncoproteins. When tumor suppressor miRNAs are experimentally over-expressed in cancer cells they inhibit their proliferation, invasion and proliferation capacity [103].

Expression profiling of miRNAs in PC have showed that some miRNAs were significantly up- or down-regulated when compared to normal prostate tissue, pointing to the importance of miRNAs in tumor progression and pathogenesis; e.g. miR-34a and miR-34c were found to have an important role in AR-dependent and p53-mediated apoptosis [104, 105]. miR-125b was an up-regulated miRNA in clinical PC samples and androgen independent cell lines; thus, its up-regulation might be related with androgen-independence and survival [103]. Another up-regulated miRNA in PC was miR-21; but, it affected tumorigenesis, invasion and metastasis by inhibiting the synthesis of proteins that normally function in these pathways. miR-21 also inhibits apoptosis [103]; and, contributes to drug resistance of PC to docetaxel treatment [106, 107]. miR-148a was defined as an androgen-responsive microRNA that promoted growth when up-regulated in the PC cell line LNCaP and one if its mRNA targets was found to be the cullin associated and neddylation-dissociated 1 (CAND1) transcript, coding for a tumor suppressor protein [108].

In contrast, miRNAs like miR-15a and miR-16-1 were found to be down-regulated in PC; their over-expression achieved by intra-cell delivery methods showed significant tumor regression capacity in vivo [103]. Other down-regulated miRNAs with tumor suppressor function in PC were miR-125b, miR-99a, miR-99b and miR-100. Again, when their expressions were restored, PSA expressions could be reduced and PC cell proliferation was inhibited [109].

miR-145 and miR-143 are tumor suppressor miRNAs that are commonly dysregulated in all cancer types. miR-145 and miR143 are also first transcribed together on a cluster and cleaved off during the miRNA maturation process. In PC miR-145 is down-regulated and over-expression of it has an anti-tumorigenic effect, resulting with the inhibition of migration and invasion of PC cells [103].

Some miRNAs take part in formation of androgen-independent PC; and, by comparing an-drogen-dependent and -independent PC samples, miR-146a has been revealed as such [110]. Finally, an example of a miRNA that is regulated by its target is miR-34a. The tumor suppressor and transcription factor p53 directly regulates the expression of miR-34a, which is decreased in CD44+ PC cells. When normally expressed it could inhibit PC regeneration and metastasis by directly repressing CD44 [111, 112]. The list of miRNAs which expressions are most significantly altered in PC are given in Table 2.

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