Exploration Of Prostate Cancer Genomics Research And The Androgen Signaling Pathway In Prostate Cancer

Prostate cancer is a common disease among men but the knowledge of the prostate carcinogenesis is still limited,cDNA microarray-based comparative genomic hybridization(CGH) and expression profiling were performed to screen the genomic and the expression changes in prostate cancer respectively.The two data were then integrated to study the influence of genomic aberrations on gene expression and seek for the genes with their expression affected by the genomic aberrations.Real-time PCR was performed to evaluate the array data.Array-based CGH detected gains at 2q,3p/q,5q,6q,8q,9p,10p/q,11q,12p,14q and 19p/q and losses at 1p,2p,4q,6p/q,7p,11p/q,12q,17p/q,19p/q and Xp/q in more than 20%prostate tumors and narrowed these aberrations.For example,the gain of 8q was mapped to five minimal regions.Novel aberrations were also identified, such as loss at Xq21.33-q22.2.Expression profiling discovered the significant biological processes involved in the prostate carcinogenesis,such as exogenous antigen presentation via MHC Classâ…¡and protein ubiquitination.Integration analysis revealed a weak positive correlation between genomic copy number and gene expression level.53 genes showed their expression directly affected by the genomic aberrations possibly,including more than one member of Ras superfamily and MHC (major histocompatibility complex).These genes are involved in multiple biological processes.Thus,we inferred that although the direct influence of genomic aberrations on gene expression seems weak,the influence can be extended by indirect regulation through a few directly affected genes.Because the influence can be persistent,the genes directly affected by the genomic aberrations may play key roles in the prostate carcinogenesis and are worth further analysis.According to the previous reports,the androgen signaling is not only crucial for the growth of the prostate cancer cells,but also plays an important role in the transformation of prostate cancer from androgen dependence to independence. However,the knowledge about the androgen signaling,especially about the androgen responsive genes,spread over the documents.For the further study on the prostate carcinogenesis,we constructed the Androgen Responsive Gene Database(ARGDB). ARGDB was devoted to providing integrated knowledge on androgen controlled genes.Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 946 original publications were manually screened.3049 genes were finally included in the database.All of them were experimentally proved to be regulated by androgen.For each gene important details of the androgen regulation experiments were collected from the references such as direction of expression change,assayed regulatory sequence,response time,tissue or cell type, method and androgen name and amount,which will facilitate the evaluation by researchers.Furthermore,the database was integrated with multiple annotation resources,including National Center for Biotechnology Information,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes Pathway,to reveal the biological characteristics and significance of androgen-regulated genes.ARGDB website is mainly constituted of the Browse,Search,Element Scan and Submission modules.It is user-friendly and freely accessible at http://argdb.fudan.edu.cn.Preliminary analysis of the collected data was performed.Many disease pathways were found to be enriched in androgen-regulated genes such as the prostate carcinogenesis.The discovered androgen response motifs were similar to the previous reports and we found the right half-site of the motifs was more conserved than the left. The analysis results were displayed in the website.In conclusion,ARGDB provides a unified gateway to storage,retrieval and update of information on androgen-regulation genes.ARGDB was employed to analyze our array data of the prostate cancer and we found a group of androgen responsive genes abnormally expressed in the prostate cancer or differentially expressed between the androgen-dependent and androgen-independent prostate cancers.These genes might play a key role in the early stage of the prostate carcinogenesis and the prostate cancer progression,especially of the transformation from androgen dependence to independence.These genes will be further studied in the future.