Androgen regulation of micro‐RNAs in prostate cancer

Abstract

BACKGROUND Androgens play a critical role in the growth of both androgen dependent and castration‐resistant prostate cancer (CRPC). Only a few micro‐RNAs (miRNAs) have been suggested to be androgen regulated. We aim to identify androgen regulated miRNAs. METHODS We utilized LNCaP derived model, we have established, and which overexpresses the androgen receptor (AR), the VCaP cell line, and 13 intact‐castrated prostate cancer (PC) xenograft pairs, as well as clinical specimens of untreated (PC) and CRPC. The expression of miRNAs was analyzed by microarrays and quantitative RT‐PCR (Q‐RT‐PCR). Transfection of pre‐miR‐141 and anti‐miR‐141 was also used. RESULTS Seventeen miRNAs were >1.5‐fold up‐ or downregulated upon dihydrotestosterone (DHT) treatment in the cell lines, and 42 after castration in the AR‐positive xenografts. Only four miRNAs (miR‐10a, miR‐141, miR‐150*, and miR‐1225‐5p) showed similar androgen regulation in both cell lines and xenografts. Of those, miR‐141 was found to be expressed more in PC and CRPC compared to benign prostate hyperplasia. Additionally, the overexpression of miR‐141 enhanced growth of parental LNCaP cells while inhibition of miR‐141 by anti‐miR‐141 suppressed the growth of the LNCaP subline overexpressing AR. CONCLUSIONS Only a few miRNAs were found to be androgen‐regulated in both cell lines and xenografts models. Of those, the expression of miR‐141 was upregulated in cancer. The ectopic overexpression of miR‐141 increased growth of LNCaP cell suggesting it may contribute to the progression of PC. Prostate 71:604–614, 2011. © 2010 Wiley‐Liss, Inc.

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

“…In the patient cohort presented in this study, the expression of the diagnostic and prognostic miR-221/222 is strongly downregulated during disease progression. Similar downregulation was observed for PCa cell lines (Waltering et al, 2011). In the latest study, only four miRNAs showed similar regulation in both, cell lines and xenograftpairs, and only miR-141 demonstrated concordant expression in castration resistant PCa clinical specimens when compared with PCa.…”

“…For example, it has been shown that elevated expression of miR-21 can enhance PCa tumor growth in vivo and, is sufficient for androgen-dependent tumors to overcome castration-mediated growth arrest (Ribas et al, 2009). We recently identified miR-21 together with miR-32, miR-141, miR-221 and miR-375 as differentially expressed during dihydrotestosterone stimulation of different PCa cell lines or 13 intact-castrated pairs of PCaxenografts (Waltering et al, 2011). It has been reported that the mir-221/222 cluster is upregulated in matched androgen-dependent and androgen-independent PCa cell lines (Sun et al, 2009).…”

“…In the latest study, only four miRNAs showed similar regulation in both, cell lines and xenograftpairs, and only miR-141 demonstrated concordant expression in castration resistant PCa clinical specimens when compared with PCa. The dissimilarity between the response of different miRNAs to androgen stimulation in cell lines and xenograft models and when compared with expression in clinical samples, may be explained by the direct response to androgens in in vitro studies compared with the long-term effects of androgen deprivation in vivo (Waltering et al, 2011). In addition, the diagnostic and prognostic profiles obtained in this study are based on clinical samples derived early, from patients with organ-confined disease, years before clinical relapse and androgen deprivation therapy.…”

Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease

“…For hsa-miR-141 and hsamiR-375, this finding is consistent with previous studies. 40,41 We propose that these miRNAs are expressed in prostate cancer cells and released into surrounding blood vessels during disease progression. Interestingly, hsa-miR-346 was elevated in the serum of men with mCRPC but reduced in metastases in the MSKCC cohort.…”

Circulating microRNAs: macro-utility as markers of prostate cancer?

“…Given that the miRNA transcriptome is profoundly affected by androgen signaling in PCa (for review, see Coppola et al (2009)), it is not surprising that androgenic regulation of many of the circulating miRNAs described earlier has been documented (e.g. miR-141 and other miR-200 family members (Szczyrba et al 2010, Waltering et al 2010, miR-375 (Szczyrba et al 2010, Waltering et al 2010, miR-21 (Shi et al 2007, Ribas et al 2009, Narayanan et al 2010, and miR-221 (Sun et al 2009)). These observations provide important mechanistic information regarding the origins of these potential biomarkers, which may be critical for their effective clinical implementation.…”