miR-21: an oncomir on strike in prostate cancer.

BACKGROUND: Aberrant expression of microRNAs, small non-coding RNA molecules that post-transcriptionally repress gene expression, seems to be causatively linked to the pathogenesis of cancer. In this context, miR-21 was found to be overexpressed in different human cancers (e.g. glioblastoma, breast cancer). In addition, it is thought to be endowed with oncogenic properties due to its ability to negatively modulate the expression of tumor-suppressor genes (e.g. PTEN) and to cause the reversion of malignant phenotype when knocked- down in several tumor models. On the basis of these findings, miR-21 has been proposed as a widely exploitable cancer-related target. However, scanty information is available concerning the relevance of miR-21 for prostate cancer. In the present study, we investigated the role of miR-21 and its potential as a therapeutic target in two prostate cancer cell lines, characterized by different miR-21 expression levels and PTEN gene status. RESULTS: We provide evidence that miR-21 knockdown in prostate cancer cells is not sufficient per se i) to affect the proliferative and invasive potential or the chemo- and radiosensitivity profiles or ii) to modulate the expression of the tumor-suppressors PTEN and Pdcd4, which in other tumor types were found to be regulated by miR-21. We also show that miR-21 is not differently expressed in carcinomas and matched normal tissues obtained from 36 untreated prostate cancer patients subjected to radical prostatectomy. CONCLUSIONS: Overall, our data suggest that miR-21 is not a central player in the onset of prostate cancer and that its single hitting is not a valuable therapeutic strategy in the disease. This supports the notion that the oncogenic properties of miR-21 could be cell and tissue dependent and that the potential role of a given miRNA as a therapeutic target should be contextualized with respect to the disease.

LEADeR role of miR-205 host gene as long noncoding RNA in prostate basal cell differentiation.

Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. Here, we show that only lowly expressed alternatively spliced MIR205HG transcripts act as de facto pri-miRNAs, through a process that involves Drosha to prevent unfavorable splicing and directly mediate miR-205 excision. Notably, MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway. At molecular level, MIR205HG directly binds the promoters of its target genes, which have an Alu element in proximity of the Interferon-Regulatory Factor (IRF) binding site, and represses their transcription likely buffering IRF1 activity, with the ultimate effect of preventing luminal differentiation. As MIR205HG functions autonomously from (albeit complementing) miR-205 in preserving the basal identity of prostate epithelial cells, it warrants reannotation as LEADeR (Long Epithelial Alu-interacting Differentiation-related RNA).

Targeting microRNAs to withstand cancer metastasis.

MicroRNAs are endogenous, regulatory, noncoding small RNAs shown to play a key role in controlling gene expression, mainly at the posttranscriptional level. Several lines of evidence highlighted the importance of selected microRNAs as essential actors of cancer initiation events, tumor progression towards malignancy, and ultimately metastasis. By acting as either prometastatic or antimetastatic factors, microRNAs may represent novel targets or tools to withstand cancer progression. This chapter summarizes the available strategies to manipulate the expression of metastasis-related microRNAs, either by mimicking or inhibiting them, in cell systems and in vivo models. In addition, we provide a broad overview of conceptual and technological issues that need to be addressed before microRNAs might be exploited in the clinical setting for the prevention and treatment of the metastatic disease.

miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells.

Compelling evidence suggests that epithelial-to-mesenchymal transition is involved in the resistance of human cancer cells to chemotherapy. We previously reported that the expression of miR-205, a miRNA down-regulated in prostate cancer, is further repressed in prostate cancer cells undergoing epithelial-to-mesenchymal transition, suggesting a possible involvement of the miRNA in the acquisition of the chemoresistant phenotype. In the present study, we show that miR-205 replacement in castration-resistant mesenchymal prostate cancer cells caused an enhancement of cisplatin cytotoxic activity in vitro and in vivo, as a consequence of autophagy impairment. Specifically, the constraints on the autophagic flux were associated to the miRNA-dependent down-regulation of the lysosome-associated proteins RAB27A and LAMP3. These findings suggest that miR-205-mediated impairment of the autophagic pathway may interfere with the detoxifying capabilities of prostate cancer cells in their attempt to cope with cisplatin-induced detrimental effects. Overall, our data indicate that (i) loss of miR-205 may indeed contribute to acquire mesenchymal tracts and concomitantly establish a permissive autophagic milieu that confers a chemotherapy resistant phenotype to prostate cancer cells, and (ii) strategies aimed at restoring miR-205 expression levels may represent a successful approach to overcome resistance of prostate cancer to platinum compounds.

MicroRNAs: cobblestones on the road to cancer metastasis.

Cancer metastasis is the product of a multistep process during which tumor cells, responding to different intrinsic and extrinsic stimuli, detach from the primary tumor mass, invade the contiguous stroma, migrate over a long distance, and colonize distant organs. Despite the well-established role of protein-coding genes behind such events, emerging evidence suggests how genetic and epigenetic alterations in microRNAs equally contribute to cancer metastasis. In this review, we retrace step-to-step all the most salient phases of the tumor dissemination process, by focusing on the role that specific microRNAs play from the time a cancer cell leaves the primary tumor until it acquires the ability to form secondary tumors at distant sites. We also provide a discussion of relevant conceptual and technological issues that need to be addressed before a microRNA-based therapy might be exploited in the clinical setting for the prevention and cure of the metastatic disease.

MicroRNA-mediated control of prostate cancer metastasis: implications for the identification of novel biomarkers and therapeutic targets.

Prostate cancer is the most prevalent tumor in the male population and the second leading cause of cancer-related death in men in Western countries. Besides genetic and epigenetic aberrations in protein coding genes, alterations in microRNAs equally contribute to prostate cancer initiation and progression. In this context, a plethora of overwhelming evidence establishes the involvement of microRNAs as essential actors in the multi-step cascade fostering a prostate cancer cell to leave the primary tumor and form secondary tumors at distant sites. Herein, we describe how specific microRNAs may impinge on the different stages of prostate cancer metastasis and review published profiling studies in which microRNA expression data have been analyzed in relation to clinical parameters of progression for the identification of novel biomarkers. We also provide evidence concerning the possibility to manipulate metastasis-related microRNA functions, either by mimicking or inhibiting them, as a highly promising strategy for the development of innovative therapeutic approaches for the advanced disease.

MicroRNAs as new therapeutic targets and tools in cancer.

INTRODUCTION: MicroRNAs (miRNAs) are a class of endogenous, non-coding small RNAs that negatively regulate gene expression at the post-transcriptional level. Several studies have provided evidence that abnormal expression of selected miRNAs is associated with the pathogenesis of cancer. As they can act as either oncogenes or tumor suppressors, miRNAs have been proposed as potential new therapeutic targets or tools for cancer therapy. AREAS COVERED: This paper reviews a significant body of the experimental data collected to date which indicate that specific miRNA inhibition or replacement can successfully modify the proliferative and invasive properties of tumor cells. It discusses recent evidence that has also revealed a direct involvement of miRNAs in drug resistance, underlying an entirely new mechanism by which tumor cells may be refractory to the treatment with cytotoxic agents. Based on these findings, in the therapeutic setting, interference with cancer-specific miRNAs could be exploited not only to produce a direct anticancer effect but also to improve the response of tumor cells to conventional treatments. EXPERT OPINION: Overall, manipulation of miRNA functions, either by mimicking or inhibiting them, is emerging as a highly promising therapeutic strategy. However, before miRNA-based therapeutics enters the clinical armamentarium, important issues concerning specific delivery to cells/tissues of interest, safety as well as pharmacokinetic profiles needs to be addressed.