MiR-21-5p in Urinary Extracellular Vesicles is a Novel Biomarker of Urothelial Carcinoma

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Feb 5

PMID 28160564

Citations 54

Authors

Kyosuke Matsuzaki

Kazutoshi Fujita

Kentaro Jingushi

Atsunari Kawashima

Takeshi Ujike

Akira Nagahara

Yuko Ueda

Go Tanigawa

Iwao Yoshioka

Koji Ueda

Rikinari Hanayama

Motohide Uemura

Yasushi Miyagawa

Kazutake Tsujikawa

Norio Nonomura

Affiliations

Soon will be listed here.

Abstract

Background: Extracellular vesicles are lipid bilayer vesicles containing protein, messengerRNA and microRNA. Cancer cell-derived extracellular vesicles may be diagnostic and therapeutic targets. We extracted extracellular vesicles from urine of urothelial carcinoma patients and the control group to identify cancer-specific microRNAs in urinary extracellular vesicles as new biomarkers.

Materials And Methods: microRNA from urinary extracellular vesicles extracted from 6 urothelial carcinoma patients and 3 healthy volunteers was analyzed. We verified candidate microRNAs in an independent cohort of 60 urinary extracellular vesicles samples. To normalize the microRNA expression level in extracellular vesicles, we examined the following in extracellular vesicles: protein concentration, CD9 intensity, amounts of whole miRNAs, RNA U6B small nuclear expression and the creatinine concentration of original urine correlating with the counts of extracted extracellular vesicles measured by the NanoSight™ system.

Results: From the microarray results 5 microRNAs overexpressed in urinary extracellular vesicles of urothelial carcinoma patients were identified. Creatinine concentration of original urine correlated most with particle counts of extracellular vesicles, indicating that creatinine could be a new tool for normalizing microRNA expression. MiR-21-5p was the most potent biomarker in urinary extracellular vesicles (sensitivity, 75.0%; specificity, 95.8%) and was also overexpressed in urinary extracellular vesicles from urothelial carcinoma patients with negative urine cytology. For the subgroup with negative urine cytology, the sensitivity was 75.0% and specificity was 95.8%.

Conclusion: MiR-21-5p in urinary extracellular vesicles could be a new biomarker of urothelial carcinoma, especially for urothelial carcinoma patients with negative urine cytology.

Citing Articles

Epigenetic Biomarkers as a New Diagnostic Tool in Bladder Cancer-From Early Detection to Prognosis.

Jaszek N, Bogdanowicz A, Siwiec J, Starownik R, Kwasniewski W, Mlak R J Clin Med. 2024; 13(23).

PMID: 39685620 PMC: 11642161. DOI: 10.3390/jcm13237159.

Extracellular Vesicles and Their Applications in Tumor Diagnostics and Immunotherapy.

Strum S, Evdokimova V, Radvanyi L, Spreafico A Cells. 2024; 13(23.

PMID: 39682778 PMC: 11639792. DOI: 10.3390/cells13232031.

Bacterial information in serum extracellular vesicles reflects the inflammation of adherent perinephric fat.

Uemura T, Kawashima A, Jingushi K, Motooka D, Saito T, Sassi N Cancer Sci. 2024; 116(2):338-349.

PMID: 39566543 PMC: 11786307. DOI: 10.1111/cas.16410.

The diagnostic accuracy of urine-derived exosomes for bladder cancer: a systematic review and meta-analysis.

Long C, Shi H, Li J, Chen L, Lv M, Tai W World J Surg Oncol. 2024; 22(1):285.

PMID: 39472962 PMC: 11520875. DOI: 10.1186/s12957-024-03569-1.

Bladder cancer: non-coding RNAs and exosomal non-coding RNAs.

Zhao J, Ma Y, Zheng X, Sun Z, Lin H, Du C Funct Integr Genomics. 2024; 24(5):147.

PMID: 39217254 DOI: 10.1007/s10142-024-01433-9.

References

Crossland R, Norden J, Bibby L, Davis J, Dickinson A . Evaluation of optimal extracellular vesicle small RNA isolation and qRT-PCR normalisation for serum and urine. J Immunol Methods. 2016; 429:39-49. DOI: 10.1016/j.jim.2015.12.011. View

Witwer K, Buzas E, Bemis L, Bora A, Lasser C, Lotvall J . Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013; 2. PMC: 3760646. DOI: 10.3402/jev.v2i0.20360. View

van Rhijn B, van der Poel H, van der Kwast T . Urine markers for bladder cancer surveillance: a systematic review. Eur Urol. 2005; 47(6):736-48. DOI: 10.1016/j.eururo.2005.03.014. View

White N, Fatoohi E, Metias M, Jung K, Stephan C, Yousef G . Metastamirs: a stepping stone towards improved cancer management. Nat Rev Clin Oncol. 2010; 8(2):75-84. DOI: 10.1038/nrclinonc.2010.173. View

Egawa H, Jingushi K, Hirono T, Ueda Y, Kitae K, Nakata W . The miR-130 family promotes cell migration and invasion in bladder cancer through FAK and Akt phosphorylation by regulating PTEN. Sci Rep. 2016; 6:20574. PMC: 4738343. DOI: 10.1038/srep20574. View

Tanaka Y, Kamohara H, Kinoshita K, Kurashige J, Ishimoto T, Iwatsuki M . Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2012; 119(6):1159-67. DOI: 10.1002/cncr.27895. View

Long J, Sullivan T, Humphrey J, Logvinenko T, Summerhayes K, Kozinn S . A non-invasive miRNA based assay to detect bladder cancer in cell-free urine. Am J Transl Res. 2016; 7(11):2500-9. PMC: 4697726. View

Liu C, Hsieh C, Shen C, Lin C, Shigemura K, Sung S . Exosomes from the tumor microenvironment as reciprocal regulators that enhance prostate cancer progression. Int J Urol. 2016; 23(9):734-44. DOI: 10.1111/iju.13145. View

Volinia S, Calin G, Liu C, Ambs S, Cimmino A, Petrocca F . A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006; 103(7):2257-61. PMC: 1413718. DOI: 10.1073/pnas.0510565103. View

10.

Akers J, Ramakrishnan V, Kim R, Skog J, Nakano I, Pingle S . MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLoS One. 2013; 8(10):e78115. PMC: 3804457. DOI: 10.1371/journal.pone.0078115. View

11.

Esteva-Font C, Wang X, Ars E, Guillen-Gomez E, Sans L, Gonzalez Saavedra I . Are sodium transporters in urinary exosomes reliable markers of tubular sodium reabsorption in hypertensive patients?. Nephron Physiol. 2010; 114(3):p25-34. PMC: 2840242. DOI: 10.1159/000274468. View

12.

Wszolek M, Rieger-Christ K, Kenney P, Gould J, Silva Neto B, Lavoie A . A MicroRNA expression profile defining the invasive bladder tumor phenotype. Urol Oncol. 2009; 29(6):794-801.e1. DOI: 10.1016/j.urolonc.2009.08.024. View

13.

Thery C, Zitvogel L, Amigorena S . Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2(8):569-79. DOI: 10.1038/nri855. View

14.

Zhang H, Qi F, Cao Y, Zu X, Chen M . Expression and clinical significance of microRNA-21, maspin and vascular endothelial growth factor-C in bladder cancer. Oncol Lett. 2015; 10(4):2610-2616. PMC: 4580005. DOI: 10.3892/ol.2015.3540. View

15.

Delic D, Eisele C, Schmid R, Baum P, Wiech F, Gerl M . Urinary Exosomal miRNA Signature in Type II Diabetic Nephropathy Patients. PLoS One. 2016; 11(3):e0150154. PMC: 4773074. DOI: 10.1371/journal.pone.0150154. View

16.

Shao Y, Shen Y, Chen T, Xu F, Chen X, Zheng S . The functions and clinical applications of tumor-derived exosomes. Oncotarget. 2016; 7(37):60736-60751. PMC: 5312416. DOI: 10.18632/oncotarget.11177. View

17.

Matullo G, Naccarati A, Pardini B . MicroRNA expression profiling in bladder cancer: the challenge of next-generation sequencing in tissues and biofluids. Int J Cancer. 2015; 138(10):2334-45. DOI: 10.1002/ijc.29895. View

18.

Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji M . Exosome mediated communication within the tumor microenvironment. J Control Release. 2015; 219:278-294. DOI: 10.1016/j.jconrel.2015.06.029. View

19.

Planz B, Jochims E, Deix T, Caspers H, Jakse G, Boecking A . The role of urinary cytology for detection of bladder cancer. Eur J Surg Oncol. 2005; 31(3):304-8. DOI: 10.1016/j.ejso.2004.12.008. View

20.

Neely L, Rieger-Christ K, Silva Neto B, Eroshkin A, Garver J, Patel S . A microRNA expression ratio defining the invasive phenotype in bladder tumors. Urol Oncol. 2008; 28(1):39-48. DOI: 10.1016/j.urolonc.2008.06.006. View