Prostate cancer gene expression signature of patients with high body mass index

Abstract

The goal of this study was to evaluate prostate cancer gene expression signatures associated with elevated body mass index (BMI). Global gene expression profiles of prostate tumor cells and matching normal epithelial cells were compared between patients with features of normal and high BMI at the time of radical prostatectomy. Knowledge-based analyses revealed an association of high BMI with altered levels of lipid metabolism and cholesterol homeostasis genes, such as stearoyl-CoA desaturase 1 (SCD1) and insulin-induced gene 1 (INSIG1), respectively, in prostate tumor cells. These genes were connected to known pathways of tumorigenesis revealed by the v-maf (musculoaponeurotic fibrosarcoma) oncogene homolog (MAF), notch receptor ligand, jagged 1 (JAG1) and the alanyl aminopeptidase (ANPEP/CD13) genes. This study highlighted that SCD1, a known target of statins, may have a mechanistic role in the recently noted beneficial effects of statin treatment in reducing biochemical recurrence of prostate cancer. An additional finding of our study is that some of the obesity-related genes were upregulated in tumor-matched normal cells within the high BMI group, when compared with normal cells within the normal BMI cohort.

Figure 1

Quantitative RT-PCR analysis of ERG, AMACR and PCA3 prostate cancer marker genes. For the quality control of LCM selected tumor and matching benign epithelial cells, RNA was isolated and ERG, AMACR and PCA3 gene expression levels were defined by QRT-PCR. T/N ratios were calculated and were log10 transformed and are represented on the heat map. Extreme green (−3) and extreme red (+3) colors denote 1000X down or 1000X upregulation, respectively.

Figure 2

Schematic diagram of bioinformatic analysis.

Figure 3

Knowledge-based pathway analysis (Genomatix BiblioSphere Software) indicating the network of high BMI-associated genes. The displayed network is constructed from 53 input genes. Connection lines are drawn as a result of co-citation of two genes within one sentence. Green or partially green connection lines indicate a transcription factor matrix match in the promoter of the gene connected by the green line. Orange or yellow indicates up-regulated, shades of blue mark down-regulated genes in the T/N data sets. Major biochemical pathways are highlighted with pink color.

Figure 4

a–e: Expression of the individual genes forming the central node of high BMI prostate cancer signature. Genes forming the central node were individually analyzed to assess the differential expression in tumor and matching benign cells. Log2 transformed gene expression signal intensities of (a) INSIG1 (p=0.0038), (b) SCD1 (p=0.0113), (c) ANPEP (p=0.0150), (d) MAF (p=0.0131) and (e) JAG1 (p=0.0081) genes are shown in box-plot diagrams representing expression signal intensity values in tumor and normal prostate epithelial cells in high and normal BMI patients.