Noncoding RNAs as Novel Biomarkers in Prostate Cancer

Table 1

Overview of prostate cancer biomarkers.

Specimens	Category	Examples	Up/down	Summary/description	Reference
Tissue	Noncoding RNAs:
	lncRNAs	PCA3	↑	PCa-specific, 66-fold upregulated in PCa-tissue compared to nonmalignant prostate tissue (in >95% of PCa patients)	[6, 18, 40–43]
		CBR3-AS1, MALAT1, PCAT1, 6, 7, 18, PCGEM1, PRNCR1, and SCHLAP1	↑	Identified overexpressed lncRNAs in PCa tissue	[23, 44–51]
	microRNAs	miR-21, miR-183/96/182	↑	Well-known oncomirs, upregulated miRNAs in several cancer tissues	[52–71, 108]
		miR-221/222	↑	Upregulated in different cancer tissue, highly expressed in CRPC tissue	[66, 72, 73]
		miR-375	↑	Upregulated in PCa tissue compared to nonmalignant tissue	[66, 109]
		miR-143/145	↓	Downregulation is associated with progression of cancers	[91–93]
		miR-205, miR-200-family	↓	Well-known tumor suppressor, downregulated in many cancer tissues, involved in EMT	[66, 74–90]
	Protein-coding genes:
	mRNAs/proteins	AMACR, caveolin-1, CD147, endoglin (CD105), human kallikrein-2, interleukin-6, PSMA, and TGF-β 1		Upregulated in PCa tissue compared to nonmalignant tissue; AMACR: upregulated in 88% of PCa, CRPC and metastasis strongly positive; CD147: overexpressed in many solid tumors; increased expression is associated with PCa progression and poor prognosis; PSMA: transmembrane glycoprotein, upregulated in PCa tissue compared to benign tissue; TGF- 1: growth factor; increased expression correlates with tumor invasion, metastasis and biochemical recurrence; human kallikrein-2: serine protease activates pro-KLK3 to its active form (PSA)	[6, 18]
	DNA modifications:
	Genetic modification	TMPRSS2-ERG fusion, BRCA1/2 mutation		TMPRSS2-ERG gene fusion: expressed in malignant prostate tissue, independent marker of disease progression and poor prognosis; BRCA1/2 are tumor suppressors; BRCA2 mutation is associated with aggressive PCa and poor survival outcome	[6, 18]
	Epigenetic modification	GSTP1, RASSF1A		GSTP1 hypermethylation was detected in 90% of prostate cancer; RASSF1A is a tumor suppressor gene; RASSF1A hypermethylation has been observed in 60–74% of PCa and in 18.5% of BPH	[18, 19]
Body fluids (blood and/or urine)	Noncoding RNAs:
	lncRNAs	PCA3	↑	PCA3 score (PCA3/KLK3 ratio) FDA approved as diagnostic biomarker for PCa (sensitivity 66%, specificity 76%)	[6, 18, 41–43]
		miR-141, miR-375, miR-21, miR-221/222	↑	upregulated in plasma/serum of PCa patients with advanced disease (metastasis and/or CRPC)	[108–130]
	microRNAs (circulating)	miR-200-family	↑	Upregulated in serum of CRPC patients; high levels were found in serum of nonresponders to docetaxel prior treatment, associated with shorter survival	[9, 111]
		miR-107, miR-574-3p	↑	Upregulated in urine of PCa patients compared to healthy controls	[112]
		miR-205, miR-214	↓	Downregulated in urine of PCa patients compared to healthy controls	[134]
	DNA modifications:
	Genetic modification	TMPRSS2:ERG fusion		Detection of TMPRSS2:ERG fusion transcript in urinary sediments, obtained after DRE (specificity 93%), combined test: PCA3 score + TMPRESS2:ERG fusion in urine after DRE—improved sensitivity from 66% (PCA3 alone) to 73% (combined)	[6, 18]
	Epigenetic modification	GSTP1		GSTP1 hypermethylation was found in postprostate massage urine sediments of 68% of PCa patients with early confined disease, 78% of patients with locally advanced PCa, 29% of patients with PIN, and 2% of patients with BPH.	[18, 19]
	Cells/vesicles:
	CTCs			Detection of CTCs in blood has the potential to evaluate disease progression and for monitoring of therapy response. The Veridex CellSearch Assay has received FDA approval for the enumeration of CTCs in prostate cancer.	[16, 165–170]
	Extracellular vesicles	Exosomes, apoptotic bodies, microvesicles, and prostasomes		Extracellular vesicles are cell-derived vesicles that can be isolated from urine and blood and have the potential as biomarker for PCa. They also contain specific DNA, RNA, and protein molecules that are unique to the cells they originate of, and these could also serve as biomarker(s).	[125, 142–150, 157]

AMACR: -methylacyl-CoA racemase; CTCs: circulating tumor cells; GSTP1: glutathione S-transferase pi 1; KLK3: kallikrein-3; lncRNAs: long noncoding RNAs; PCa: prostate cancer; PSA: prostate-specific antigen; PSMA: prostate-specific membrane antigen.