BACKGROUND: There is no standard serum biomarker used for diagnosis or early detection of recurrence for renal cell carcinoma (RCC) patients. MicroRNAs (miRNAs) are abundant and highly stable in blood serum, and have been recently described as powerful circulating biomarkers in a wide range of solid cancers. Our aim was to identify miRNA signature that can distinguish the blood serum of RCC patients and matched healthy controls and validate identified miRNAs as potential biomarkers for RCC. METHODS: In the screening phase of the study, blood serum of 15 RCC patients and 12 matched healthy controls were analyzed by use of the TaqMan Low-Density Arrays enabling parallel identification of expression levels of 667 miRNAs through qRT-PCR-based approach. In the validation phase, identified miRNAs were further evaluated on the independent group of 90 RCC patients and 35 matched healthy controls by use of individual qRT-PCR assays and statistically evaluated. RESULTS: We identified 30 miRNAs differentially expressed between serum of RCC patients and healthy controls: 19 miRNAs were up-regulated and 11 miRNAs were down-regulated in RCC patients. MiR-378, miR-451 and miR-150 were further evaluated in the independent group of patients, and two of them were successfully validated: levels of miR-378 were increased (p = 0.0003, AUC = 0.71), miR-451 levels were decreased (p < 0.0001, AUC = 0.77) in serum of RCC patients. Combination of miR-378 and miR-451 enable identification of RCC serum with the sensitivity of 81%, specificity 83% and AUC = 0.86. CONCLUSIONS: Circulating miRNAs in serum are promising biomarkers in RCC.

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Zluty kopec 7 Brno Czech Republic

Zobrazit více v PubMed

Yi Z, Fu Y, Zhao S, Zhang X, Ma C. Differential expression of miRNA patterns in renal cell carcinoma and nontumorous tissues. J Cancer Res Clin Oncol. 2010;136:855–862. doi: 10.1007/s00432-009-0726-x. PubMed DOI PMC

Chow TF, Youssef YM, Lianidou E, Romaschin AD, Honey RJ, Stewart R, Pace KT, Yousef GM. Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin Biochem. 2010;43:150–158. doi: 10.1016/j.clinbiochem.2009.07.020. PubMed DOI

Ljungberg B. Prognostic markers in renal cell carcinoma. Curr Opin Urol. 2007;17:303–308. doi: 10.1097/MOU.0b013e328277f180. PubMed DOI

Slaby O, Jancovicova J, Lakomy R, Svoboda M, Poprach A, Fabian P, Kren L, Michalek J, Vyzula R. Expression of miRNA-106b in conventional renal cell carcinoma is a potential marker for prediction of early metastasis after nephrectomy. J Exp Clin Cancer Res. 2010;29:90. doi: 10.1186/1756-9966-29-90. PubMed DOI PMC

Slaby O, Svoboda M, Michalek J, Vyzula R. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009;8:102. doi: 10.1186/1476-4598-8-102. PubMed DOI PMC

Redova M, Svoboda M, Slaby O. MicroRNAs and their target gene networks in renal cell carcinoma. Biochem Biophys Res Commun. 2010;405:153–156. PubMed

Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110:13–21. doi: 10.1016/j.ygyno.2008.04.033. PubMed DOI

Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–269. doi: 10.1038/nrc1840. PubMed DOI

Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS, Hatton CS, Harris AL. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 2008;141:672–675. doi: 10.1111/j.1365-2141.2008.07077.x. PubMed DOI

Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X. Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer. 2010;127:118–126. doi: 10.1002/ijc.25007. PubMed DOI

Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE. The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol. 2009;112:55–59. doi: 10.1016/j.ygyno.2008.08.036. PubMed DOI

Roth C, Rack B, Muller V, Janni W, Pantel K, Schwarzenbach H. Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res. 2010;12:R90. doi: 10.1186/bcr2766. PubMed DOI PMC

Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–10518. doi: 10.1073/pnas.0804549105. PubMed DOI PMC

Wulfken LM, Moritz R, Ohlmann C, Holdenrieder S, Jung V, Becker F, Herrmann E, Walgenbach-Brunagel G, von Ruecker A, Muller SC, Ellinger J. MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS One. 2011;6:e25787. doi: 10.1371/journal.pone.0025787. PubMed DOI PMC

Reimers M, Carey VJ. Bioconductor: an open source framework for bioinformatics and computational biology. Methods Enzymol. 2006;411:119–134. PubMed

Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS, Sung JJ. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009;58:1375–1381. doi: 10.1136/gut.2008.167817. PubMed DOI

Mosakhani N, Sarhadi VK, Borze I, Karjalainen-Lindsberg ML, Sundstrom J, Ristamaki R, Osterlund P, Knuutila S. MicroRNA profiling differentiates colorectal cancer according to KRAS status. Genes Chromosomes Cancer. 2012;51:1–9. doi: 10.1002/gcc.20925. PubMed DOI

Scapoli L, Palmieri A, Lo Muzio L, Pezzetti F, Rubini C, Girardi A, Farinella F, Mazzotta M, Carinci F. MicroRNA expression profiling of oral carcinoma identifies new markers of tumor progression. Int J Immunopathol Pharmacol. 2010;23:1229–1234. PubMed

Wang P, Fu T, Wang X, Zhu W. Primary, study of miRNA expression patterns in laryngeal carcinoma by microarray. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2010;24:535–538. PubMed

Bandres E, Bitarte N, Arias F, Agorreta J, Fortes P, Agirre X, Zarate R, Diaz-Gonzalez JA, Ramirez N, Sola JJ, Jimenez P, Rodriguez J, Garcia-Foncillas J. microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells. Clin Cancer Res. 2009;15:2281–2290. doi: 10.1158/1078-0432.CCR-08-1818. PubMed DOI

Wu Q, Jin H, Yang Z, Luo G, Lu Y, Li K, Ren G, Su T, Pan Y, Feng B, Xue Z, Wang X, Fan D. MiR-150 promotes gastric cancer proliferation by negatively regulating the pro-apoptotic gene EGR2. Biochem Biophys Res Commun. 2010;392:340–345. doi: 10.1016/j.bbrc.2009.12.182. PubMed DOI

Flamant S, Ritchie W, Guilhot J, Holst J, Bonnet ML, Chomel JC, Guilhot F, Turhan AG, Rasko JE. Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia. Haematologica. 2010;95:1325–1333. doi: 10.3324/haematol.2009.020636. PubMed DOI PMC

Ma Y, Zhang P, Wang F, Zhang H, Yang J, Peng J, Liu W, Qin H. miR-150 as a potential biomarker associated with prognosis and therapeutic outcome in colorectal cancer. Gut. 2011. in press doi:10.1136/gutjnl-2011-301122. PubMed

Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–2261. doi: 10.1073/pnas.0510565103. PubMed DOI PMC

Youssef YM, White NM, Grigull J, Krizova A, Samy C, Mejia-Guerrero S, Evans A, Yousef GM. Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur Urol. 2011;59:721–730. doi: 10.1016/j.eururo.2011.01.004. PubMed DOI

Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, Shen H. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol. 2010;28:1721–1726. doi: 10.1200/JCO.2009.24.9342. PubMed DOI

Reid G, Kirschner MB, van Zandwijk N. Circulating microRNAs: Association with disease and potential use as biomarkers. Crit Rev Oncol Hematol. 2011;80:193–208. doi: 10.1016/j.critrevonc.2010.11.004. PubMed DOI

Grinchuk OV, Jenjaroenpun P, Orlov YL, Zhou J, Kuznetsov VA. Integrative analysis of the human cis-antisense gene pairs, miRNAs and their transcription regulation patterns. Nucleic Acids Res. 2010;38:534–547. doi: 10.1093/nar/gkp954. PubMed DOI PMC

Zhao H, Shen J, Medico L, Wang D, Ambrosone CB, Liu S. A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS One. 2010;5:e13735. doi: 10.1371/journal.pone.0013735. PubMed DOI PMC

Tsujiura M, Ichikawa D, Komatsu S, Shiozaki A, Takeshita H, Kosuga T, Konishi H, Morimura R, Deguchi K, Fujiwara H, Okamoto K, Otsuji E. Circulating microRNAs in plasma of patients with gastric cancers. Br J Cancer. 2010;102:1174–1179. doi: 10.1038/sj.bjc.6605608. PubMed DOI PMC

Silva J, Garcia V, Zaballos A, Provencio M, Lombardia L, Almonacid L, Garcia JM, Dominguez G, Pena C, Diaz R, Herrera M, Varela A, Bonilla F. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J. 2011;37:617–623. doi: 10.1183/09031936.00029610. PubMed DOI

Circulating Non-coding RNAs in Renal Cell Carcinoma-Pathogenesis and Potential Implications as Clinical Biomarkers

Combination of MiR-378 and MiR-210 Serum Levels Enables Sensitive Detection of Renal Cell Carcinoma

MicroRNAs in urine are not biomarkers of multiple myeloma