Detailed Technical Analysis of Urine RNA-Based Tumor Diagnostics Reveals ETS2/Urokinase Plasminogen Activator to Be a Novel Marker for Bladder Cancer

Hanke, Merle; Kausch, Ingo; G, Dahmen; Jocham, Dieter; Warnecke, Jens M.

doi:10.1373/clinchem.2007.091363

Cited by 42 publications

(31 citation statements)

References 31 publications

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“…In consequence, the analytical focus on sediments as done in several studies does not let expect satisfying results. A similar phenomenon of differences between samples of whole urine, cell-depleted urine, and sediments was also observed in bladder cancer patients for various mRNAs [9]. In addition, the differences in that study were not uniform for all tested mRNAs but showed a particular behavior for specific mRNAs [9].…”

supporting

confidence: 70%

“…A similar phenomenon of differences between samples of whole urine, cell-depleted urine, and sediments was also observed in bladder cancer patients for various mRNAs [9]. In addition, the differences in that study were not uniform for all tested mRNAs but showed a particular behavior for specific mRNAs [9]. Thus, the focus on possible new urinary markers including noncoding nucleic acids like microRNAs, long non-coding RNAs, and piRNAs should draw attention to this aspect.…”

supporting

confidence: 62%

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The way of prostate cancer diagnostics

Stephan¹,

Jung²

2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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Prostate cancer diagnostics has been essentially changed within the last 5 years. While prostate-specific antigen (PSA) remains the basic parameter, the additional value of the two 2012 FDA-approved biomarkers prostate health index (PHI) in serum and prostate cancer gene 3 (PCA3) in urine has been confirmed numerous times [1]. The detection of TMPRSS2-ERG gene fusions in the tissue of approximately 50% of all prostate cancer patients and the subsequently developed urinary assay [2] put hope on further diagnostic improvement that could unfortunately only be partially fulfilled [3][4][5].The senior author of this article [6] in this issue of Clinical Chemistry and Laboratory Medicine played the key role in detecting PCA3 and developing urinary assays for PCA3 and TMPRSS2-ERG [7]. And this group is now the first that compared both markers in whole urine, urinary sediment and exosomes. With this new independent study, the authors completed and partly relativized previous data when they compared only the profile of these markers in urinary sediments and exosomes [8]. This comparative approach between various urine fractions can be considered as exemplary for testing other biomarkers not only for prostate cancer but also for renal cell carcinoma and bladder cancer. The positive effect of a digital rectal examination (DRE) of the prostate before urine sampling for diagnostic purpose was confirmed regarding the diagnostic validity of these markers in detecting prostate cancer. However, the main result was that whole urine results in a higher analytical sensitivity compared to sensitivity obtained using sediments and exosomes. In this respect, the advantage to use whole urine samples as applied in the tests for PCA3 and TMPRSS2-ERG instead sediments is not only justified from the practical point of view but also with regard to the improved analytical sensitivity. On the other hand, biomarker levels measured in the three tested urine fractions in this study and presented in table 4 proved that there was a distinct difference between the levels in the whole urine and the sum of the two other fractions [6]. Thus, it can be concluded that a great amount of these mRNAs in the urine obviously occurs in free forms without any association to particles (exosomes) and without cellular confinement (sediments). It is particularly worth mentioning that this comprehensively researched study by Hendriks et al. clears away the erroneous view that nucleic acids in urine as in this case of PCA3 mRNA and TMPRSS2-ERG mRNA are mostly detected in the released prostate cells. In consequence, the analytical focus on sediments as done in several studies does not let expect satisfying results. A similar phenomenon of differences between samples of whole urine, cell-depleted urine, and sediments was also observed in bladder cancer patients for various mRNAs [9]. In addition, the differences in that study were not uniform for all tested mRNAs but showed a particular behavior for specific mRNAs [9]. Thus, the focus on possible new urinary markers in...

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supporting

confidence: 70%

supporting

confidence: 62%

The way of prostate cancer diagnostics

Stephan¹,

Jung²

2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…55 Hypermethylation of the caveolin-1 gene and abnormal caveolin-1 protein expression have crucial roles in cell differentiation and in the phonotypical conversion of TCC into nonurothelial carcinomas. 56 Among the transcription factors that were studied at promoter pull-down analysis with the nuclear extract from murine sham and PBOO BSM tissues, transcription factor Ets-2 is overexpressed in human bladder cancer, 57 and SP-1 regulates tumor necrosis factor-␣-induced MMP-9 expression through ERK1/2 and p38 MAP kinase in bladder cancer cells. 58 However, in murine and human obstructed BSM tissues, Ets-2 and SP-1 are not overexpressed.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Repression of Caveolin-1 (CAV1) Gene Expression by GATA-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings

Boopathi

Gomes

Goldfarb

et al. 2011

The American Journal of Pathology

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Hypertrophy occurs in urinary bladder wall smooth muscle (BSM) in men with partial bladder outlet obstruction (PBOO) caused by benign prostatic hyperplasia (BPH) and in animal models of PBOO. Hypertrophied BSM from the rabbit model exhibits downregulation of caveolin-1, a structural and functional protein of caveolae that function as signaling platforms to mediate interaction between receptor proteins and adaptor and effector molecules to regulate signal generation, amplification, and diversification. Caveolin-1 expression is diminished in PBOO-induced BSM hypertrophy in mice and in men with BPH. The proximal promoter of the human and mouse caveolin-1 (CAV1) gene was characterized, and it was observed that the transcription factor GATA-6 binds this promoter, causing reduced expression of caveolin-1. Furthermore, caveolin-1 expression levels inversely correlate with the abundance of GATA-6 in BSM hypertrophy in mice and human beings. Benign prostatic hyperplasia (BPH) is common in aging men and is often associated with lower urinary tract symptoms. Partial bladder outlet obstruction (PBOO) has long been considered a key factor in the mechanism through which BPH causes lower urinary tract symptoms. PBOO-induced lower urinary tract symptoms are associated with bladder wall smooth muscle (BSM) remodeling including hypertrophy, thereby altering bladder contractility.

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“…However, in urine we can found a significant amounts of cell-free RNA and for this reason RNA tumor markers (e.g., hTERT, UPK1A, HTATIP2), cannot be used unconditionally for RT-qPCR-based analysis of whole urine [97]. Another system that has been intensively studied for its role in tumorigenesis is uPA: ETS2.…”

Section: Rna Messengermentioning

confidence: 99%

“…In the case of bladder cancer higher ETS2 RNA concentration it is observed compared with uPA. This tumor marker ratio of ETS2: uPA could be an interesting diagnostic tool [97][98][99][100][101]. Hedegaard et al prepared a total RNA-sequencing (RNA-seq) libraries for 476 patients with bladder cancer at different stages (Ta, T1, in situ [CIS], MIBC).…”

Section: Rna Messengermentioning

confidence: 99%

Bladder Cancer Markers and Recent Innovations

Viola-Magni¹,

Cataldi²,

Marocco³

2017

Bladder Cancer - Management of NMI and Muscle-Invasive Cancer

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Bladder cancer (urothelial carcinoma) is the most common tumor of the urinary tract. It occurs more frequently among men about 65 years old on average. Two forms of the tumor are known: a non-muscle-invasive one and a muscle-invasive one. The latter turns out to be very aggressive with a survival of 5 years average. The non-muscle-invasive form frequently recurs (60-70%) and in 15% of cases, it progresses into the invasive form. The diagnosis is made mainly by cystoscopy and urine cytology. A high number of researches were dedicated in order to find a simple test using voided urine to frequently monitor possible tumor recurrence. During the last 10 years, many tests were proposed concerning either special proteins of which the most common are the bladder tumor antigen (BTA) and the nuclear matrix protein 22 (NMP22) or the presence of genetic mutations [most frequently, fibroblasts growth factor receptor 3 (FGFR3) and TP53], alteration of DNA methylation, chromatin structure and, more recently, the presence of specific micro-RNA. Recently the analysis of lipids present in voided urine showed a difference in fatty acids between healthy individuals and those affected by non-invasive forms. These markers appear to have a high specificity and sensitivity: a deepening of these results could lead to the development of a test that avoids invasive treatment and the cost of cystoscopy.

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Detailed Technical Analysis of Urine RNA-Based Tumor Diagnostics Reveals ETS2/Urokinase Plasminogen Activator to Be a Novel Marker for Bladder Cancer

Cited by 42 publications

References 31 publications

The way of prostate cancer diagnostics

The way of prostate cancer diagnostics

Transcriptional Repression of Caveolin-1 (CAV1) Gene Expression by GATA-6 in Bladder Smooth Muscle Hypertrophy in Mice and Human Beings

Bladder Cancer Markers and Recent Innovations

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