The Prostate Cancer-up-regulated Long Noncoding RNA PlncRNA-1Modulates Apoptosis And Proliferation Through Reciprocal Regulation Of Androgen Receptor

Backgroud and ObjectiveProstate cancer (CaP) is a prevalent malignancy in American men, with217,730estimated new cases that occurred in2010and almost32,050deaths. Early stage CaPuniquely relies on androgens for proliferation, and blockade of the androgen receptor (AR)pathway almost invariably induces tumor regression. However, in later stages, CaP cellsbecome androgen-independent, and no curative therapy exists for this refractorydisease.AR reactivation plays an important role in the procession. AR pathwayhyperactivation can result from hypersensitivity to androgen, aberrant androgen synthesis,abnormal activation by co-regulator alterations, or alternative pathways, such as growthfactors, receptor tyrosine kinases. Identification of genes involved in the transition fromandrogen-dependent to androgen-independent prostate cancer (AIPC) is important toextend our current knowledge of AIPC. Mammalian genomes transcribe a wide array ofRNA molecules. In addition to the classic long protein coding mRNAs, more recently,short regulatory noncoding RNAs (e.g., microRNAs, small interfering RNAs) and longnon-coding RNAs (lncRNAs,>200nucleotides) were characterized. lncRNAs are known toplay important roles during cellular development and their misregulation has also beenshown in various types of cancers including breast cancer, colon cancer, CaP,hepatocellular carcinoma, and leukemia. Recent studies have revealed the contribution oflncRNAs as protooncogenes, tumor suppressor genes, and drivers of metastatictransformation, for example GAGE6, p15, and HOTAIR. Emerging evidences implicatelong noncoding RNAs (lncRNAs) are deregulated in cancer development. The purpose ofthe current study is to investigate the role of new lncRNA, named PlncRNA-1, in prostatecancer (CaP) pathogenesis.Materials and MethodsIn this study, real-time q-PCR was used to demonstrate the expression of PlncRNA-1in16pairs CaP tissues and matched normal tissues,14pairs CaP tissues and BPH tissues,4CaP cell lines, including LNCaP, LNCaP-AI, PC3, and C4-2, and2normal prostate epithelial cell lines RWPE-1and PWR-1E. After PlncRNA-1was suppressed by siRNA inLNCaP and LNCaP-AI cell lines, cell proliferation and apoptosis were assessed usingCCK-8and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). AfterPlncRNA-1and 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 ofPlncRNA-1and AR.ResultsWe showed that expression of PlncRNA-1was signifcantly higher in CaP cellsrelative to normal prostate epithelial cells, as well as higher in human CaPs compared withnormal tissues and benign prostatic hyperplasia (BPH). Silencing of PlncRNA-1signifcantly reduced cell proliferation and induced apoptosis in CaP cell lines LNCaP andLNCaP-AI. Mechanistically, PlncRNA-1suppression by siRNA resulted in a decrease ofandrogen receptor (AR) mRNA, protein and AR downstream target. Of note, blockade ofAR signaling with siRNA also resulted in a suppression of PlncRNA-1expression in CaPcell lines.ConclusionsOur study demonstrated that PlncRNA-1is involved in prostate tumorigenesis. Thereciprocal regulation of PlncRNA-1and androgen receptor contribute to CaP pathogenesisSilencing of PlncRNA-1inhibits cell growth and induces apoptosis in bothandrogen-dependent and androgen-independent CaP cells, suggesting PlncRNA-1may befurther evaluated as a promising therapeutic target in CaP.