Long noncoding RNA MALAT-1 is a new potential therapeutic target for castration resistant prostate cancer.

To understand the role of MALAT-1 in prostate cancer we evaluated its expression in prostate cancer tissues and cell lines. We also studied the therapeutic effects of MALAT-1 silencing on castration resistant prostate cancer cells in vitro and in vivo. Quantitative reverse transcriptase-polymerase chain reaction was used to detect MALAT-1 expression in prostate cancer tissues and cell lines. siRNA against MALAT-1 was designed and the silencing effect was examined by quantitative reverse transcriptase-polymerase chain reaction. The biological effects of MALAT-1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays as well as cell migration by in vitro scratch assay, cell invasion by Transwell® invasion assay and cell cycle by flow cytometry. We further investigated the effect of therapeutic siRNA targeting MALAT-1 on castration resistant prostate cancer in vivo. MALAT-1 was up-regulated in human prostate cancer tissues and cell lines. Higher MALAT-1 expression correlated with high Gleason score, prostate specific antigen, tumor stage and castration resistant prostate cancer. MALAT-1 down-regulation by siRNA inhibited prostate cancer cell growth, invasion and migration, and induced castration resistant prostate cancer cell cycle arrest in the G0/G1 phases. Importantly, intratumor delivery of therapeutic siRNA targeting MALAT-1 elicited delayed tumor growth and reduced metastasis of prostate cancer xenografts in castrated male nude mice, followed by the concomitant prolongation of survival of tumor bearing mice. MALAT-1 may be needed to maintain prostate tumorigenicity and it is involved in prostate cancer progression. Thus, MALAT-1 may serve as a potential therapeutic target for castration resistant prostate cancer.

Ren S ，Liu Y ，Xu W ，Sun Y ，Lu J ，Wang F ，Wei M ，Shen J ，Hou J ，Gao X ，Xu C ，Huang J ，Zhao Y ，Sun Y ... -  《-》

The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor.

Emerging evidences implicate long noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose of the current study is to investigate the role of new lncRNA, named PlncRNA-1, in prostate cancer (CaP) pathogenesis. In this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1 in 16 pairs CaP tissues and matched normal tissues, 14 pairs CaP tissues and BPH tissues, 4 CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and 2 normal prostate epithelial cell lines RWPE-1 and PWR-1E. After PlncRNA-1 was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed using CCK-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). After PlncRNA-1 and AR was suppressed by siRNA in LNCaP and LNCaP-AI cell lines, real-time q-PCR and Western blotting were used to measure reciprocal regulation of PlncRNA-1 and AR. We showed that expression PlncRNA-1, was significantly higher in CaP cells relative to normal prostate epithelial cells, as well as higher in human CaPs compared with normal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1 significantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP and LNCaP-AI. Mechanistically, PlncRNA-1 suppression by siRNA resulted in a decrease of androgen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade of AR signaling with siRNA also resulted in a suppression of PlncRNA-1 expression in CaP cell lines. Our study suggests reciprocal regulation of PlncRNA-1 and androgen receptor contribute to CaP pathogenesis and that PlncRNA-1 is a potential therapy target.

Cui Z ，Ren S ，Lu J ，Wang F ，Xu W ，Sun Y ，Wei M ，Chen J ，Gao X ，Xu C ，Mao JH ，Sun Y ... -  《-》

LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer.

Wang D ，Ding L ，Wang L ，Zhao Y ，Sun Z ，Karnes RJ ，Zhang J ，Huang H ... -  《Oncotarget》

PDLIM2 suppression efficiently reduces tumor growth and invasiveness of human castration-resistant prostate cancer-like cells.

Although PDLIM2 gene may have a context-dependent role in various human malignancies and can be a potential therapeutic target, only a limited number of in vitro studies addressed the molecular functions of PDLIM2 in prostate cancer. Here, we aimed to explore the role of PDLIM2 and the effect of the PDLIM2 gene suppression on oncogenic phenotypes of human castration-resistant prostate cancer (CRPC)-like cells. We used human CRPC-like cell lines (PC3, DU145, and C4-2B) for our experiments. Transcription levels of PDLIM2 and relevant genes were measured by real time-PCR and protein expression was analyzed by western blot. Cell viability, proliferation, clonogenic growth, and tumor sphere formation were examined after a specific inhibition of PDLIM2 using RNA interference. Flow cytometry was used to examine apoptotic cell death and cell cycle disturbances. Wound healing and transwell migration assays were performed to investigate the invasion capabilities of CRPC-like cells. Additionally, key oncogenic signaling pathways were examined using western blot. Lastly, we evaluated the in vivo efficacy of PDLIM2 suppression on tumor growth of human CRPC xenografts in mice. We observed a significant enhancement of PDLIM2 expression in human CRPC-like cell lines, while a specific inhibition of PDLIM2 reduced cell viability and proliferation due to apoptotic cell death. Conversely, PDLIM2 overexpression significantly reduced cell proliferation compared to the negative control in androgen-sensitive LNCaP cells. Moreover, PDLIM2 suppression led to a decrease of clonogenic growth and tumor sphere formation in three-dimensional cultures with the G2/M cell cycle arrest in human CRPC-like cells. PDLIM2 inhibition also attenuated cellular migration and invasion capabilities of human CRPC-like cells, and reduced the expression of mesenchymal marker. Among several oncogenic signaling pathways, only the MAPK/ERK signaling cascade was decreased by PDLIM2 inhibition and reciprocally, ERK inhibition down-regulated PDLIM2 expression. Importantly, PDLIM2 inhibition remarkably compromised tumor growth in a human CRPC xenograft model. In summary, the suppression of PDLIM2 significantly reduced such oncogenic phenotypes as proliferation, clonogenicity, invasiveness, and tumor cell growth in human CRPC-like cells both in vitro and in vivo, indicating that PDLIM2 may be considered a novel therapeutic target gene for treating human CRPC.

Kang M ，Lee KH ，Lee HS ，Park YH ，Jeong CW ，Ku JH ，Kim HH ，Kwak C ... -  《-》

S100A3 suppression inhibits in vitro and in vivo tumor growth and invasion of human castration-resistant prostate cancer cells.

To investigate the role of S100A3 and the effect of S100A3 inhibition on human castration-resistant prostate cancer (CRPC) cells by using in vitro and in vivo functional assays. Using human CRPC cells (PC3 and DU145), S100A3 expression levels were assessed by reverse transcription-polymerase chain reaction and Western blot analysis. After S100A3-specific small interfering ribonucleic acid (RNA) treatment, cell viability was determined by Cell Counting Kit-8 assay, and apoptotic cell fractions were evaluated by flow cytometry. The invasive properties of these cells and the expression pattern of matrix metalloproteinases (MMPs) were assessed using transwell migration assays, reverse transcription-polymerase chain reaction, and gelatin zymography. Finally, the in vivo efficacy of S100A3 inhibition on human CRPC cells was investigated using human tumor xenograft models in nude mice. Human CRPC cells showed overexpression of S100A3, and its suppression reduced cell viability owing to apoptotic cell death. Additionally, S100A3 inhibition decreased the invasiveness of human CRPC cells. Moreover, MMP-2 and MMP-9 were downregulated in PC3, whereas only MMP-9 was downregulated in D145 after S100A3 inhibition. In human CRPC xenograft models, we noted a marked reduction in tumor growth in mice injected with S100A3 short hairpin RNA-transfected PC3 and DU145 cells. Human CRPC cells showed upregulation of S100A3 expression, and S100A3 inhibition reduced tumor cell viability. S100A3 inhibition reduced invasion capability with downregulation of MMP expression. More importantly, S100A3 inhibition resulted in tumor growth suppression in human CRPC xenograft models, suggesting S100A3 could serve as a novel therapeutic target for the treatment of human CRPC.

Kang M ，Lee HS ，Lee YJ ，Choi WS ，Park YH ，Jeong CW ，Ku JH ，Kim HH ，Kwak C ... -  《-》