The translational potential of microRNAs as biofluid markers of urological tumours

Fendler, Annika; Stephan, Carsten; Yousef, George M.; Kristiansen, Glen; Jung, Klaus

doi:10.1038/nrurol.2016.193

Cited by 112 publications

(109 citation statements)

References 133 publications

(99 reference statements)

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“…These include extracellular vesicles [29], long noncoding RNAs [30,31], microRNAs [32,33,34] and circulating tumor cells (CTCs) [35,36], among many others. These advances have provided new insights into the individual patient’s tumor biology, and several biomarkers with specific indications for disease diagnosis, prediction and prognosis, as well as risk stratification of aggressive PCa at the time of diagnosis are now commercially available.…”

Section: Introductionmentioning

confidence: 99%

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Kulkarni

Uversky

2017

IJMS

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A clinical dilemma in the management of prostate cancer (PCa) is to distinguish men with aggressive disease who need definitive treatment from men who may not require immediate intervention. Accurate prediction of disease behavior is critical because radical treatment is associated with high morbidity. Here, we highlight the cancer/testis antigens (CTAs) as potential PCa biomarkers. The CTAs are a group of proteins that are typically restricted to the testis in the normal adult but are aberrantly expressed in several types of cancers. Interestingly, >90% of CTAs are predicted to belong to the realm of intrinsically disordered proteins (IDPs), which do not have unique structures and exist as highly dynamic conformational ensembles, but are known to play important roles in several biological processes. Using prostate-associated gene 4 (PAGE4) as an example of a disordered CTA, we highlight how IDP conformational dynamics may regulate phenotypic heterogeneity in PCa cells, and how it may be exploited both as a potential biomarker as well as a promising therapeutic target in PCa. We also discuss how in addition to intrinsic disorder and post-translational modifications, structural and functional variability induced in the CTAs by alternate splicing represents an important feature that might have different roles in different cancers. Although it is clear that significant additional work needs to be done in the outlined direction, this novel concept emphasizing (multi)functionality as an important trait in selecting a biomarker underscoring the theranostic potential of CTAs that is latent in their structure (or, more appropriately, the lack thereof), and casts them as next generation or “smart” biomarker candidates.

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Section: Introductionmentioning

confidence: 99%

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Kulkarni

Uversky

2017

IJMS

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“…The association of microRNAs with prostate cancer has been extensively reviewed elsewhere (Thieu et al , 2014; Fabris et al , 2016; Fendler et al , 2016). Studies of tumours or biofluids of patients have resulted in the identification of several microRNAs as potential biomarkers of prostate cancer.…”

mentioning

confidence: 99%

“…The levels of these three microRNAs were elevated in tumours and/or biofluids of prostate cancer patients vs healthy controls. These microRNAs were also elevated in tumours and/or biofluids of patients with metastatic compared to those with localised prostate cancer, where high levels of miR-375 was associated with poor survival in CRPC (Thieu et al , 2014; Fabris et al , 2016; Fendler et al , 2016). Only a few studies have investigated the potential of circulating microRNAs as therapeutic response biomarkers in CRPC (Gonzales et al , 2011; Zhang et al , 2011; Cheng et al , 2013).…”

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confidence: 99%

Phase 2 study of circulating microRNA biomarkers in castration-resistant prostate cancer

et al. 2017

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Background:Biomarkers of therapeutic response and prognosis are needed to assist in the sequencing of treatments for metastatic castration-resistant prostate cancer (CRPC). Previously in a Phase 1 discovery study, we identified 14 circulating microRNAs that were associated with response to docetaxel chemotherapy or overall survival. We performed a Phase 2 validation study to verify these findings.Methods:Using real-time PCR, the levels of the 14 microRNAs were measured in plasma collected before and after the first cycle of docetaxel from a Phase 2 cohort of 89 patients.Results:The microRNAs were not associated with docetaxel response in the Phase 2 cohort. Higher baseline levels of six microRNAs, predominantly of the miR-200 family, were confirmed to be associated with shorter overall survival. A microRNA signature comprising these six microRNAs predicted high-risk patients in the Phase 2 cohort with a hazard ratio of 4.12 (95% CI 2.20–7.70, P=0.000001). The signature was an independent predictor in multivariable analysis with clinicopathological factors.Conclusions:The association of circulating microRNAs with overall survival suggests their involvement in CRPC progression.

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“…15 On the basis of the literature reviews and gene target prediction databases, including TargetScan (http://www.targetscan.org/), miRanda (http://www.microrna.org/), and miRBASE (http://www.mirbase.org/), we hypothesized that Wnt3a may be a potential target of miR-491-5p. The Wnt3a gene is an important member of the Wnt ligand family, which exerts its function by activating the canonical Wnt signaling pathway.…”

mentioning

confidence: 99%

miR-491-5p, mediated by Foxi1, functions as a tumor suppressor by targeting Wnt3a/β-catenin signaling in the development of gastric cancer

et al. 2017

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Accumulated evidence has suggested that microRNAs (miRNAs) have an important role in tumor development and progression by regulating diverse signaling pathways. However, the precise role of miRNAs in gastric cancer (GC) has not been elucidated. In this study, we describe the function and regulation network of miR-491-5p in GC. miR-491-5p is frequently downregulated in GC tissues compared with adjacent non-cancerous tissues. Forced expression of miR-491-5p significantly inhibits proliferation and colony formation, and promotes apoptosis in GC cells. Through bioinformatic analysis and luciferase assays, we confirm that miR-491-5p targets Wnt3a. Silencing Wnt3a inhibits cell proliferation and induces apoptosis. Similarly, restoration of Wnt3a counteracts the effects of miR-491-5p expression. Moreover, bioinformatic and luciferase assays indicate that the expression of miR-491-5p is regulated by Foxi1, which binds to its promoter and activates miR-491-5p expression. In conclusion, to the best of our knowledge, our findings are the first to demonstrate that Foxi1 is a key player in the transcriptional control of miR-491-5p and that miR-491-5p acts as an anti-oncogene by targeting Wnt3a/β-catenin signaling in GC. Our study reveals that Foxi1/miR-491-5p/Wnt3a/β-catenin signaling is critical in the progression of GC. Targeting the pathway described in this study may open up new prospects to restrict the progression of GC.

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The translational potential of microRNAs as biofluid markers of urological tumours

Cited by 112 publications

References 133 publications

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Cancer/Testis Antigens: “Smart” Biomarkers for Diagnosis and Prognosis of Prostate and Other Cancers

Phase 2 study of circulating microRNA biomarkers in castration-resistant prostate cancer

miR-491-5p, mediated by Foxi1, functions as a tumor suppressor by targeting Wnt3a/β-catenin signaling in the development of gastric cancer

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