The prostate-specific proteome
The prostate is a gland of the male reproductive system. The function of the prostate is to produce fluid that together with fluid from seminal vesicles and sperm from the testis constitute semen. The prostate is composed of secretory glands and a specific smooth muscle rich fibro-muscular stroma. The transcriptome analysis shows that 70% of all human proteins (n=20344) are expressed in the prostate and 159 of these genes show an elevated expression in prostate compared to other tissue types.
An analysis of the genes with elevated expression in the prostate shows that the corresponding proteins are expressed in the glandular compartment of the prostatic tissue.
- 21 prostate enriched genes
- Most of the enriched genes encode for secreted or membranous proteins
- 159 genes defined as elevated in the prostate
- Most group enriched genes share expression with testis and cerebral cortex
Figure 1. The distribution of all genes across the five categories based on transcript abundance in prostate as well as in all other tissues.
159 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.
Table 1. The genes with elevated expression in prostate
Number of genes
||At least five-fold higher mRNA levels in a particular tissue as compared to all other tissues
||At least five-fold higher mRNA levels in a group of 2-7 tissues
||At least five-fold higher mRNA levels in a particular tissue as compared to average levels in all tissues
||Total number of elevated genes in prostate
Table 2. The 12 genes with the highest level of enriched expression in prostate. "Predicted localization" shows the classification of each gene into three main classes: Secreted, Membrane, and Intracellular, where the latter consists of genes without any predicted membrane and secreted features. "mRNA (tissue)" shows the transcript level as FPKM values, TS-score (Tissue Specificity score) corresponds to the score calculated as the fold change to the second highest tissue.
||kallikrein-related peptidase 3
||kallikrein-related peptidase 2
||kallikrein-related peptidase 4
||acid phosphatase, prostate
||cholinergic receptor, nicotinic, alpha 2 (neuronal)
||solute carrier family 45, member 3
||olfactory receptor, family 51, subfamily E, member 2
||Sp8 transcription factor
||ret finger protein-like 2
Some of the proteins predicted to be membrane-spanning are intracellular, e.g., in the Golgi or mitochondrial membranes, and some of the proteins predicted to be secreted can potentially be retained in a compartment belonging to the secretory pathway, such as the ER, or remain attached to the outer face of the cell membrane by a GPI anchor.
The prostate transcriptome
An analysis of the expression levels of each gene makes it possible to calculate the relative mRNA pool for each of the categories. The analysis shows that 83% of the mRNA molecules in the prostate correspond to housekeeping genes and only 5% of the mRNA pool corresponds to genes categorized to be either enriched in prostate, group enriched, or prostate enhanced. Thus, most of the transcriptional activity in the prostate relates to proteins with presumed housekeeping functions as they are found in all tissues and cells analyzed.
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.
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 are secretory cells that are separated from the basement membrane and stroma by a layer of basal cells. The stroma is composed by fibro-muscular stroma, supplying blood vessels and nerves. The prostate enriched genes are expressed by the glandular cells of the prostate.
Of the 21 prostate enriched genes in prostate, three genes belong to the kalikrein protein family which is a subgroup of serine proteases having different physiological functions. One example is KLK3 most commonly 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 liquefaction of seminal fluid in the seminal coagulum and to allow sperm to swim freely. In prostate cancer and other disorders involving the prostate, the level of PSA is often elevated in the extracellular fluid and in blood. PSA in blood is a well-known biomarker for prostate cancer. Additional genes with specific expression in the prostate are KLK4, a member of the kalikrein 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 ACPP, also 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.
Genes shared between prostate and other tissues
There are 50 group-enriched genes expressed in the prostate. Group enriched genes are defined as genes showing a 5-fold higher average level of mRNA expression in a group of 2-7 tissues, including prostate, compared to all other tissues.
In order to illustrate the relation of prostate tissue to other tissue types, a network plot was generated, displaying the number of commonly expressed genes 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 4 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.
The prostate does not share any substantial number of genes with any of the other specific tissue types but most group enriched genes are shared with testis and cerebral cortex. One example of a group enriched gene between prostate, rectum and colon is the transcription factor HOXB13 which is highly conserved among vertebrates and essential for vertebrate embryonic development.
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 the reproductive function of the male. The fluid produced by the prostate is a protective and nourishing vehicle for sperm cells. Prostatic secretion consists of lipids, proteolytic enzymes, acid phosphatase, fibrolysin 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.
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 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, fibro-muscular stroma, capsule and also supplying blood vessels and nerves. The specific fibro-muscular 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.
Here, the protein-coding genes expressed in the prostate are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize protein expression patterns of proteins that correspond to genes with elevated expression in the prostate.
Transcript profiling and RNA-data analyses based on normal human tissues have been described previously (Fagerberg et al., 2013). Analyses of mRNA expression including over 99% of all human protein-coding genes was performed using deep RNA sequencing of 122 individual samples corresponding to 32 different human normal tissue types. RNA sequencing results of 4 fresh frozen tissues representing normal prostate was compared to 118 other tissue samples corresponding to 31 tissue types, in order to determine genes with elevated expression in prostate. A tissue-specific score, defined as the ratio between mRNA levels in prostate compared to the mRNA levels in all other tissues, was used to divide the genes into different categories of expression.
These categories include: genes with elevated expression in prostate, genes expressed in all tissues, genes with a mixed expression pattern, genes not expressed in prostate, and genes not expressed in any tissue. Genes with elevated expression in prostate were further sub-categorized as i) genes with enriched expression in prostate, ii) genes with group enriched expression including prostate and iii) genes with enhanced expression in prostate.
Human tissue samples used for protein and mRNA expression analyses were collected and handled in accordance with Swedish laws and regulation and obtained from the Department of Pathology, Uppsala University Hospital, Uppsala, Sweden as part of the sample collection governed by the Uppsala Biobank. All human tissue samples used in the present study were anonymized in accordance with approval and advisory report from the Uppsala Ethical Review Board.
Relevant links and publications
Uhlen et al (2015). Tissue-based map of the human proteome. Science.
Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics
Histology dictionary - prostate