title: High-throughput transcriptomic and RNAi analysis identifies AIM1, ERGIC1, TMED3 and TPX2 as potential drug targets in prostate cancer.
abstract: Prostate cancer is a heterogeneous group of diseases and there is a need for more efficient and targeted methods of treatment. In this study, the potential of gene expression data and RNA interference technique were combined to advance future personalized prostate cancer therapeutics. To distinguish the most promising in vivo prevalidated prostate cancer drug targets, a bioinformatic analysis was carried out using genome-wide gene expression data from 9873 human tissue samples. In total, 295 genes were selected for further functional studies in cultured prostate cancer cells due to their high mRNA expression in prostate, prostate cancer or in metastatic prostate cancer samples. Second, RNAi based cell viability assay was performed in VCaP and LNCaP prostate cancer cells. Based on the siRNA results, gene expression patterns in human tissues and novelty, endoplasmic reticulum function associated targets AIM1, ERGIC1 and TMED3, as well as mitosis regulating TPX2 were selected for further validation. AIM1, ERGIC1, and TPX2 were shown to be highly expressed especially in prostate cancer tissues, and high mRNA expression of ERGIC1 and TMED3 associated with AR and ERG oncogene expression. ERGIC1 silencing specifically regulated the proliferation of ERG oncogene positive prostate cancer cells and inhibited ERG mRNA expression in these cells, indicating that it is a potent drug target in ERG positive subgroup of prostate cancers. TPX2 expression associated with PSA failure and TPX2 silencing reduced PSA expression, indicating that TPX2 regulates androgen receptor mediated signaling. In conclusion, the combinatorial usage of microarray and RNAi techniques yielded in a large number of potential novel biomarkers and therapeutic targets, for future development of targeted and personalized approaches for prostate cancer management.
authors: VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors: Paula
authors: P
authors: Vainio
authors: John-Patrick
authors: JP
authors: Mpindi
authors: Pekka
authors: P
authors: Kohonen
authors: Vidal
authors: V
authors: Fey
authors: Tuomas
authors: T
authors: Mirtti
authors: Kalle A
authors: KA
authors: Alanen
authors: Merja
authors: M
authors: Perälä
authors: Olli
authors: O
authors: Kallioniemi
authors: Kristiina
authors: K
authors: Iljin
mesh_terms: D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics*; D003459:Crystallins / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C105445:CRYBG1 protein, human; D018797:Cell Cycle Proteins; D003459:Crystallins; C494448:ERGIC1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C577103:TMED3 protein, human; C122167:TPX2 protein, human; D033921:Vesicular Transport Proteins