Identification of genes that are dysregulated in androgen-independent growth of human prostate cancer

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Prostate cancer is the second leading cause of cancer-related deaths and the most common tumor occurring in American men. Although prostate cancer can often be diagnosed at an early stage, our understanding of the mechanisms of prostate tumor growth control and progression remains incomplete, limiting the treatment options. Clinically, prostate cancer progresses from an initial localized stage to an invasive and metastatic disease. Treatment of metastatic prostate cancer with androgen-ablation often elicits dramatic tumor regression, but during the course of time, most tumors acquire androgen-independence making the clinical recurrence inevitable. Identification of the differential gene expression in androgen-sensitive vs. androgen-independent cancer may yield useful biomarkers for diagnosis, prognosis, and follow-up for an early indication of relapse. In addition, novel gene targets can also be recognized for cancer therapy. In the present study, we utilized LNCaP, an in-vitro prostate cancer progression model, and Affymetrix gene-chip microarray for global expression profiling of the genes that may potentially be implicated in the acquisition of androgen-independent phenotype. The LNCaP cell model recapitulates many genetic, epigenetic and phenotypic changes associated with the progression of prostate cancer from an androgen-dependent to androgen-independent stage. We further utilized microarray data to perform a pathway prediction analysis using web-based software ‘Ingenuity pathway analysis’ and identified genetic networks associated with the advancement of prostate cancer. Among the important differentially-expressed genes identified in our analysis were Hepatocyte growth factor (HGF) and its receptor (MET), vimentin (VIM), TWIST1, activated leucocyte-cell adhesion molecule (ALCAM), intercellular adhesion molecule1 (ICAM1), activating transcription factor 3 (ATF3), trans-membrane phosphatase with tensin homology (TPTE), sprouty2 (SPRY2), protein phosphatase 2A and 2B, TIP30, tumor endothelial marker (TEM8) and suppressors of cytokine signaling 1 and 2 (SOCS1 and 2). These genes are associated with growth and proliferation, apoptotic resistance, cell invasiveness, metastasis and angiogenesis. Further analysis of the gene-expression data indicate that apoptotic/growth arrest signaling pathways (TP53, TP73, p16, etc.) are perturbed during the progression to an androgen-independent phenotype, which in turn, enable the prostate tumor cells to survive androgen-deprivation. Additional studies are warranted to exploit the clinical significance of this study by exploring the biological relevance of identified genes and delineating the molecular mechanisms of their action in prostate cancer.