Abstract
Cell-free microRNAs (miRNAs) stably and abundantly exist in body fluids and emerging evidence suggests cell-free miRNAs as a novel class of noninvasive disease biomarkers. In this study, we hypothesized that the quantitative detection of the oncogenic miR-106b-25 cluster in urine could be a useful clinical biomarker for bladder cancer (BCa). Three members of the miR-106b-25 cluster (miR-106b, miR-93 and miR-25) were quantified by real-time RT-PCR in urine supernatant of 112 BCa patients and 78 age-matched controls. In our study, the urinary levels of miR-106b were significantly higher in BCa patients than controls (P < 0.001). No significant difference was observed in the urinary levels of miR-93 and miR-25 between two groups. Furthermore, the levels of urinary miR-106b were significantly reduced in postoperative samples compared with the levels in the preoperative samples (P = 0.007). With respect of clinicopathological characteristics, the level of urinary miR-106b was associated with advanced tumor stage. Receiver operating characteristic (ROC) analysis revealed that urinary miR-106b had considerable diagnostic accuracy, yielding an AUC (the areas under the ROC curve) of 0.802 with 76.8 % sensitivity and 72.4 % specificity in differentiating BCa from controls. In conclusion, our data indicate that urinary cell-free miR-106b might provide new complementary tumor biomarkers for BCa.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi:10.3322/caac.20107.
Kirkali Z, Chan T, Manoharan M, Algaba F, Busch C, Cheng L, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology. 2005;66(6 Suppl 1):4–34. doi:10.1016/j.urology.2005.07.062.
Prout GR Jr. Barton BA, Griffin PP, Friedell GH. Treated history of noninvasive grade 1 transitional cell carcinoma. The National Bladder Cancer Group. J Urol. 1992;148(5):1413–9.
Pagano F, Bassi P, Galetti TP, Meneghini A, Milani C, Artibani W, et al. Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol. 1991;145(1):45–50.
Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2008;54(2):303–14. doi:10.1016/j.eururo.2008.04.051.
Stenzl A, Cowan NC, De Santis M, Jakse G, Kuczyk MA, Merseburger AS, et al. The updated EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2009;55(4):815–25. doi:10.1016/j.eururo.2009.01.002.
van Rhijn BW. Considerations on the use of urine markers for bladder cancer. Eur Urol. 2008;53(5):880–1. doi:10.1016/j.eururo.2008.01.043.
Vrooman OP, Witjes JA. Urinary markers in bladder cancer. Eur Urol. 2008;53(5):909–16. doi:10.1016/j.eururo.2007.12.006.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.
Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, Zepeniuk M, et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol. 2008;26(4):462–9. doi:10.1038/nbt1392.
Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids–the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8(8):467–77. doi:10.1038/nrclinonc.2011.76.
Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutat Res. 2011;717(1–2):85–90. doi:10.1016/j.mrfmmm.2011.03.004.
Gilad S, Meiri E, Yogev Y, Benjamin S, Lebanony D, Yerushalmi N, et al. Serum microRNAs are promising novel biomarkers. PLoS One. 2008;3(9):e3148. doi:10.1371/journal.pone.0003148.
Wang G, Tam LS, Li EK, Kwan BC, Chow KM, Luk CC, et al. Serum and urinary free microRNA level in patients with systemic lupus erythematosus. Lupus. 2011;20(5):493–500. doi:10.1177/0961203310389841.
Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56(11):1733–41. doi:10.1373/clinchem.2010.147405.
Hasselmann DO, Rappl G, Tilgen W, Reinhold U. Extracellular tyrosinase mRNA within apoptotic bodies is protected from degradation in human serum. Clin Chem. 2001;47(8):1488–9.
Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285(23):17442–52. doi:10.1074/jbc.M110.107821.
Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA. 2011;108(12):5003–8. doi:10.1073/pnas.1019055108.
Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13(4):423–33. doi:10.1038/ncb2210.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–33. doi:10.1038/nature03552.
Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13(3):272–86. doi:10.1016/j.ccr.2008.02.013.
Kan T, Sato F, Ito T, Matsumura N, David S, Cheng Y, et al. The miR-106b-25 polycistron, activated by genomic amplification, functions as an oncogene by suppressing p21 and Bim. Gastroenterology. 2009;136(5):1689–700.
Hudson RS, Yi M, Esposito D, Glynn SA, Starks AM, Yang Y, et al. MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene. 2013;32(35):4139–47. doi:10.1038/onc.2012.424.
Liu Y, Zhang Y, Wen J, Liu L, Zhai X, Liu J, et al. A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma. PLoS One. 2012;7(2):e32230. doi:10.1371/journal.pone.0032230.
Han Y, Chen J, Zhao X, Liang C, Wang Y, Sun L, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing. PLoS One. 2011;6(3):e18286. doi:10.1371/journal.pone.0018286.
Li X, Chen J, Hu X, Huang Y, Li Z, Zhou L, et al. Comparative mRNA and microRNA expression profiling of three genitourinary cancers reveals common hallmarks and cancer-specific molecular events. PLoS One. 2011;6(7):e22570. doi:10.1371/journal.pone.0022570.
Lin T, Dong W, Huang J, Pan Q, Fan X, Zhang C, et al. MicroRNA-143 as a tumor suppressor for bladder cancer. J Urol. 2009;181(3):1372–80. doi:10.1016/j.juro.2008.10.149.
Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, et al. Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res. 2009;37(5):1672–81. doi:10.1093/nar/gkp002.
Petrocca F, Vecchione A, Croce CM. Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor beta signaling. Cancer Res. 2008;68(20):8191–4. doi:10.1158/0008-5472.can-08-1768.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–8. doi:10.1006/meth.2001.1262.
Yun SJ, Jeong P, Kim WT, Kim TH, Lee YS, Song PH, et al. Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer. Int J Oncol. 2012;41(5):1871–8. doi:10.3892/ijo.2012.1622.
Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105(30):10513–8. doi:10.1073/pnas.0804549105.
Luo Y, Wang C, Chen X, Zhong T, Cai X, Chen S, et al. Increased serum and urinary microRNAs in children with idiopathic nephrotic syndrome. Clin Chem. 2013;59(4):658–66. doi:10.1373/clinchem.2012.195297.
Argyropoulos C, Wang K, McClarty S, Huang D, Bernardo J, Ellis D, et al. Urinary microRNA profiling in the nephropathy of type 1 diabetes. PLoS One. 2013;8(1):e54662. doi:10.1371/journal.pone.0054662.
Yamada Y, Enokida H, Kojima S, Kawakami K, Chiyomaru T, Tatarano S, et al. MiR-96 and miR-183 detection in urine serve as potential tumor markers of urothelial carcinoma: correlation with stage and grade, and comparison with urinary cytology. Cancer Sci. 2011;102(3):522–9. doi:10.1111/j.1349-7006.2010.01816.x.
Miah S, Dudziec E, Drayton RM, Zlotta AR, Morgan SL, Rosario DJ, et al. An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer. Br J Cancer. 2012;107(1):123–8. doi:10.1038/bjc.2012.221.
Wang G, Tam LS, Kwan BC, Li EK, Chow KM, Luk CC, et al. Expression of miR-146a and miR-155 in the urinary sediment of systemic lupus erythematosus. Clin Rheumatol. 2012;31(3):435–40. doi:10.1007/s10067-011-1857-4.
Wang G, Tam LS, Li EK, Kwan BC, Chow KM, Luk CC, et al. Serum and urinary cell-free MiR-146a and MiR-155 in patients with systemic lupus erythematosus. J Rheumatol. 2010;37(12):2516–22. doi:10.3899/jrheum.100308.
Hamilton AJ. MicroRNA in erythrocytes. Biochem Soc Trans. 2010;38(Pt 1):229–31. doi:10.1042/bst0380229.
Smith AL, Iwanaga R, Drasin DJ, Micalizzi DS, Vartuli RL, Tan AC, et al. The miR-106b-25 cluster targets Smad7, activates TGF-beta signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer. Oncogene. 2012;31(50):5162–71. doi:10.1038/onc.2012.11.
Shen G, Jia H, Tai Q, Li Y, Chen D. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis. 2013;34(1):211–9. doi:10.1093/carcin/bgs320.
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This work was supported by National Natural Science Foundation of China (Nos. 81271916; 81301506); Shandong Province Natural Science Foundation of China (ZR2013HQ063) and National Key Clinical Medical Specialties Foundation.
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Zhou, X., Zhang, X., Yang, Y. et al. Urinary cell-free microRNA-106b as a novel biomarker for detection of bladder cancer. Med Oncol 31, 197 (2014). https://doi.org/10.1007/s12032-014-0197-z
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DOI: https://doi.org/10.1007/s12032-014-0197-z