Molecular mechanisms of metastasis in prostate cancer.
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ABSTRACT:
SUBMITTER: Clarke NW
PROVIDER: S-EPMC3735202 | biostudies-other | 2009 Jan
REPOSITORIES: biostudies-other
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Project description:The present study aimed to screen potential genes associated with metastatic prostate cancer (PCa), in order to improve the understanding of the mechanisms underlying PCa metastasis. The GSE3325 microarray dataset, which was downloaded from the Gene Expression Omnibus database, consists of seven clinically localized PCa samples, six hormone-refractory metastatic PCa samples and six benign prostate tissue samples. The Linear Models for Microarray Data package was used to identify differentially-expressed genes (DEGs) and a hierarchical cluster analysis for DEGs was performed with the pheatmap package. Furthermore, potential functions for the DEGs were predicted by a functional enrichment analysis. Subsequently, microRNAs (miRNAs) potentially involved in the regulation of PCa metastasis were identified by WebGestalt software, and the miRNA-DEG regulatory network was visualized using Cytoscape. In addition, a pathway enrichment analysis for DEGs in the regulatory network was performed. A total of 306 and 2,073 genes were differentially expressed in the clinically localized PCa and the metastatic PCa groups, respectively, as compared with the benign prostate group, of which 174 were differentially expressed in both groups. A number of the DEGs, including CAMK2D and SH3BP4, were significantly enriched in the cell cycle, and others, such as MAF, were associated with the regulation of cell proliferation. Furthermore, some DEGs (CAMK2D and PCDH17) were observed to be regulated by miR-30, whereas others (ADCY2, MAF, SH3BP4 and PCDH17) were modulated by miR-182. Additionally, ADCY2 and CAMK2D were distinctly enriched in the calcium signaling pathway. The present study identified novel DEGs, including ADCY2, CAMK2D, MAF, SH3BP4 and PCDH17, that may be involved in the metastasis of PCa.
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Project description:Metastatic cancer remains largely incurable and fatal. The general course of cancer, from the initiation of primary tumor formation and progression to metastasis, is a multistep process wherein tumor cells at each step must display specific phenotypic features. Distinctive capabilities required for primary tumor initiation and growth form the foundation, and sometimes may remain critical, for subsequent metastases. These phenotypic features must remain easily malleable during the acquisition of additional capabilities unique and essential to the metastatic process such as dissemination to distant tissues wherein tumor cells interact with foreign microenvironments. Thus, the metastatic phenotype is a culmination of multiple genetic and epigenetic alterations and subsequent selection for favorable traits under the pressure of ever-changing tumor microenvironments. Although our understanding of the molecular programs that drive cancer metastasis are incomplete, increasing evidence suggests that successful metastatic colonization relies on the dissemination of cancer stem cells (CSCs) with tumor-regenerating capacity and adaptive programs for survival in distant organs. In the past 2-3 years, a myriad of novel molecular regulators and determinants of prostate cancer metastasis have been reported, and in this Perspective, we comprehensively review this body of literature and summarize recent findings regarding cell autonomous molecular mechanisms critical for prostate cancer metastasis.
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Project description:BackgroundCyclin A1 is a cell cycle regulator that has been implicated in the progression of prostate cancer. Its role in invasion and metastasis of this disease has not been characterized.MethodsImmunohistochemistry and cDNA microarray analyses were used to assess protein and mRNA expression of cyclin A1 and proteins with roles in metastasis, including vascular endothelial growth factor (VEGF), metalloproteinase 2 (MMP2), and MMP9, in human prostate cancer. Transient transfection and infection with viral vectors expressing cyclin A1 and short hairpin RNA (shRNA) targeting cyclin A1 were used to study the effects of altered cyclin A1 expression in PC3 prostate cancer cells. The BrdU assay, annexin V staining, and invasion chambers were used to examine cyclin A1 effects on proliferation, apoptosis, and invasion, respectively. The role of cyclin A1 and androgen receptor (AR) in transcription of VEGF and MMP2 was assessed by promoter mutation and chromatin immunoprecipitation. The effect of cyclin A1 expression on tumor growth and metastasis was analyzed in a mouse model of metastasis. All statistical tests were two-sided.ResultsCyclin A1 protein and mRNA expression were statistically significantly higher in prostate cancers than in adjacent benign tissues. A statistically significant correlation between expression of cyclin A1 and of MMP2, MMP9, and VEGF was observed in prostate tumors from 482 patients (P values from Spearman rank correlation tests < .001). PC3 cells that overexpressed cyclin A1 showed increased invasiveness, and inhibition of cyclin A1 expression via shRNA expression reduced invasiveness of these cells. Eight of 10 mice (80%) bearing PC3 cells overexpressing cyclin A1 had infiltration of tumor cells in lymph node, liver, and lung, but all 10 mice bearing tumors expressing control vector were free of liver and lung metastases and only one mouse from this group had lymph node metastasis (P values from Fisher exact tests < .001). Cyclin A1, in concert with AR, bound to and increased expression from the VEGF and MMP2 promoters.ConclusionsCyclin A1 contributes to prostate cancer invasion by modulating the expression of MMPs and VEGF and by interacting with AR.
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