The prostate-specific proteome

The prostate transcriptome

Transcriptome analysis of the prostate can be visualized with regard to the specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the prostate compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

• Tissue enriched: At least four-fold higher mRNA level in prostate compared to any other tissues.
• Group enriched: At least four-fold higher average mRNA level in a group of 2-5 tissues compared to any other tissue.
• Tissue enhanced: At least four-fold higher mRNA level in prostate compared to the average level in all other tissues.

Distribution, on the other hand, visualizes how many genes have, or do not have, detectable levels (nTPM≥1) of transcribed mRNA molecules in the prostate compared to other tissues. As evident in Table 1, all genes elevated in prostate are categorized as:

• Detected in single: Detected in a single tissue
• Detected in some: Detected in more than one but less than one-third of tissues
• Detected in many: Detected in at least a third but not all tissues
• Detected in all: Detected in all tissues

Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in prostate as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (nTPM≥1) in prostate as well as in all other tissues.

As shown in Figure 1, 127 genes show some level of elevated expression in the prostate compared to other tissues. The three categories of genes with elevated expression in prostate compared to other organs are shown in Table 1. In Table 2, the 12 genes with the highest enrichment in prostate are defined.

Table 1. The number of genes in the subdivided categories of elevated expression in prostate.

Table 2. The 12 genes with the highest level of enriched expression in prostate. "Tissue distribution" describes the transcript detection (nTPM≥1) in prostate as well as in all other tissues. "mRNA (tissue)" shows the transcript level in prostate as nTPM values. "Tissue specificity score (TS)" corresponds to the fold-change between the expression level in prostate and the tissue with the second-highest expression level.

Protein expression of genes elevated in prostate

In-depth analysis of the elevated genes in prostate using antibody-based protein profiling allowed us to create a map of where these proteins are expressed within the prostate, including the glandular cells of the prostate.

Proteins specifically expressed in glandular cells of the prostate

The prostate is composed of prostatic glands and a non-glandular stroma. Within the glandular structures there are secretory cells, which are separated from the basement membrane and stroma by a layer of basal cells. The stroma is composed by fibromuscular stroma, supplying blood vessels and nerves. The prostate enriched genes are expressed by the glandular cells of the prostate.

Of the 14 prostate enriched genes, three genes belong to the kallikrein protein family which is a subgroup of serine proteases that all have different physiological functions. One example is KLK3, generally referred to as prostate specific antigen (PSA), a serine protease that is synthesized by glandular cells of the prostate. Under normal conditions, PSA is secreted into the extracellular fluid in small quantities and its function is believed to be important for liquefaction of seminal fluid in the seminal coagulum and to allow sperm to swim freely. The serum levels of PSA are often elevated in prostate cancer, and other prostate disorders, making it a widely used biomarker for early detection in patients with prostate cancer. Additional genes with specific expression in the prostate are KLK4, another member of the kallikrein protein family, TGM4, encoding an enzyme that catalyzes the cross-linking of proteins and the conjugation of polyamines to specific proteins in the seminal tract and ACP3, an enzyme that catalyzes the conversion of orthophosphoric monoester to alcohol and orthophosphate synthesized under androgen regulation and secreted by the epithelial cells of the prostate gland.

KLK3
KLK4

TGM4
ACP3

Gene expression shared between prostate and other tissues

There are 28 group enriched genes expressed in prostate. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including prostate, compared to all other tissues.

To illustrate the relation of prostate tissue to other tissue types, a network plot was generated, displaying the number of genes with a shared expression between different tissue types.

Figure 2. An interactive network plot of the prostate enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of prostate enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 5 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

The prostate does not share group enriched gene expression of any substantial number of genes with any of the other tissue types, but most group enriched gene expression is shared with the brain, testis, and intestine. One example of a group enriched gene expressed in both prostate and brain is SLC14A1, which is described in processes within prostate cancer. Another example of a group enriched gene expressed in the prostate and intestine is HOXB13, which is involved in processes in prostate cancer and colorectal cancer.

SLC14A1 - prostate
SLC14A1 - cerebral cortex

HOXB13 - prostate
HOXB13 - rectum

Prostate function

The function of the human prostate is to produce approximately one third of the fluid that makes up semen. Together with sperm and fluid from seminal vesicles, the prostatic fluid contributes to the composition of semen, which is necessary for male reproductive function. The fluid produced by the prostate is a protective and nourishing vehicle for sperm cells. Prostatic secretion consists of lipids, proteolytic enzymes, acid phosphatase, fibrinolysin and citric acids. The seminal vesicles are located behind the prostate and insert into the prostatic gland to secrete seminal vesicle fluids into the urethra. The prostate also contains smooth muscle which helps expel semen during ejaculation.

Prostate histology

The prostate is composed of four distinct glandular regions where the peripheral zone comprises 70% and the central zone 25% of the prostate mass. The glandular component of the prostate is composed of ducts and acini, which are morphologically identical and both appear to function as dispensable reservoirs. The entire duct-acinar system is lined by a pseudostratified columnar epithelium with secretory cells. The size and structure of these glandular elements are distinctly different in the different zones of the prostate. As with other glandular organs, the secretory cells throughout the prostate are separated from the basement membrane and stroma by a layer of basal cells. The non-glandular components of the prostate include the pre-prostatic sphincter, fibromuscular stroma, capsule and also supplying blood vessels and nerves. The specific fibromuscular stroma is composed of large compact bundles of smooth muscle cells that are arranged in a random orientation and often separated by bands of dense fibrous tissue.

The histology of human prostate including detailed images and information about the different cell types can be viewed in the Protein Atlas Histology Dictionary.

Background

Here, the protein-coding genes expressed in prostate are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in prostate.

Transcript profiling was based on a combination of two transcriptomics datasets (HPA and GTEx), corresponding to a total of 14590 samples from 54 different human normal tissue types. The final consensus normalized expression (nTPM) value for each tissue type was used for the classification of all genes according to the tissue-specific expression into two different categories, based on specificity or distribution.

Relevant links and publications

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu NY et al., Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res. (2015)
PubMed: 26117540 DOI: 10.1093/nar/gkv608

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

O'Hurley G et al., Analysis of the Human Prostate-Specific Proteome Defined by Transcriptomics and Antibody-Based Profiling Identifies TMEM79 and ACOXL as Two Putative, Diagnostic Markers in Prostate Cancer. PLoS One. (2015)
PubMed: 26237329 DOI: 10.1371/journal.pone.0133449

Histology dictionary - prostate