A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma

Cheng Wang, Jicheng Hu, Meiling Lu, Hongwei Gu, Xiaojun Zhou, Xi Chen, Ke Zen, Chen-Yu Zhang, Tiehui Zhang, Jingping Ge, Junjun Wang, Chunni Zhang, Cheng Wang, Jicheng Hu, Meiling Lu, Hongwei Gu, Xiaojun Zhou, Xi Chen, Ke Zen, Chen-Yu Zhang, Tiehui Zhang, Jingping Ge, Junjun Wang, Chunni Zhang

Abstract

Circulating microRNAs (miRNAs) are emerging as clinically useful tools for cancer detection; however, little is known about their early diagnostic impact on RCC. The levels of 754 serum miRNAs were initially determined using a TaqMan Low Density Array in two pooled samples from 25 RCC and 25 noncancer controls. Markedly dysregulated miRNAs in RCC cases were subsequently validated individually by qRT-PCR in another 107 patients and 107 controls arranged in two sets. The serum levels of miR-193a-3p, miR-362 and miR-572 were significantly increased whereas the levels of miR-28-5p and miR-378 were markedly decreased in patients with RCC, even in those with stage I disease, compared with the noncancer controls (P < 0.01). The areas under the ROC curve (AUCs) for the 5 combined miRNAs were 0.807 (95% CI, 0.687-0.928) and 0.796 (95% CI, 0.724-0.867) for the training set and the validation set, respectively. Furthermore, the panel enabled the differentiation of stage I RCC from controls with AUC of 0.807 (95% CI, 0.731-0.871), a sensitivity of 80% and a specificity of 71%. This panel of 5 serum miRNA may have the potential to be used clinically as an auxiliary diagnostic tool for the early detection of RCC.

Figures

Figure 1. An overview of study design…
Figure 1. An overview of study design strategy.
Figure 2. The relative contents of 5…
Figure 2. The relative contents of 5 identified serum miRNAs in RCC cases at different stages enrolled in the training and validation sets.
The relative contents of 5 identified serum miRNAs in 76 stage I, 16 stage II, 2 stage III, 8 stage grade IV and 5 unknown stage RCC patients and 107 noncancer controls using a qRT-PCR assay (A–E). The contents of the miRNAs were normalized to let-7d/g/i and calculated using the 2−ΔΔCq method. Each point represents the mean of triplicate samples. Each P-value was derived from a nonparametric Mann–Whitney U-test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
Figure 3. The ROC curve analysis for…
Figure 3. The ROC curve analysis for discriminative ability between RCC cases and noncancer controls by the 5-miRNA panel.
ROC curves for the 5-miRNA panel to separate 28 RCC cases from 28 controls in the training set (A), 79 RCC cases from 79 controls in the validation set (B), 76 stage I RCC cases from 107 controls in the training and validation sets (C) and 92 stage I–II RCC cases from 107 controls in the training and validation sets (D).

References

    1. Eble J. N., Togashi K. & Pisani P. [Renal cell carcinoma] Pathology & Genetics: Tumors of the urinary system and male genital organs. [Eble, J. N., Sauter, G., Epstein, J. I. & Sesterhen, I. A. (ed.)] [1–87] (IARC, Lyon, 2004).
    1. Rini B. I., Campbell S. C. & Escudier B. Renal cell carcinoma. Lancet 373, 1119–1132 (2009).
    1. Gottardo F. et al. MicroRNA profiling in kidney and bladder cancers. Urol Oncol 25, 387–392 (2007).
    1. Siegel R., Naishadham D. & Jemal A. Cancer statistics. CA Cancer J Clin 62, 10–29 (2012).
    1. Banumathy G. & Cairns P. Signaling pathways in renal cell carcinoma. Cancer Biol Ther 10, 658–664 (2010).
    1. Ljungberg B. et al. European Association of Urology Guideline Group EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol 58, 398–406 (2010).
    1. Weng L. et al. MicroRNA profiling of clear cell renal cell carcinoma by whole- genome small RNA deep sequencing of paired frozen and formalin-fixed, paraffin-embedded tissue specimens. J Pathol 222, 41–51 (2010).
    1. Schaefer A., Stephan C., Busch J., Yousef G. M. & Jung K. Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors. Nat Rev Urol 7, 286–297 (2010).
    1. Chen X. et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18, 997–1006 (2008).
    1. Mitchell P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105, 10513–10518 (2008).
    1. Zhang C. et al. Expression profile of microRNAs in serum: A fingerprint for esophageal squamous cell carcinoma. Clin Chem 56, 1871–1879 (2010).
    1. Liu R. et al. Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin Chem 58, 610–618 (2012).
    1. Wulfken L. M. et al. MicroRNAs in renal cell carcinoma: Diagnostic implications of serum miR-1233 levels. PLoS One 6, e25787 (2011).
    1. Redova M. et al. Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med 10, 1–8 (2012).
    1. Hauser S. et al. Analysis of serum microRNAs (miR-26a-2*, miR-191, miR-337-3p and miR-378) as potential biomarkers in renal cell carcinoma. Cancer Epidemiol 36, 391–394 (2012).
    1. Zhai Q. et al. Identification of miR-508-3p and miR-509-3p that are associated with cell invasion and migration and involved in the apoptosis of renal cell carcinoma. Biochem Biophys Res Commun 419, 621–626 (2012).
    1. Zhao A., Li G., Péoc'h M., Genin C. & Giqante M. Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp Mol Pathol 94, 115–120 (2013).
    1. Cheng T. et al. Differential microRNA expression in renal cell carcinoma. Oncol Lett 6, 769–776 (2013).
    1. Teixeira A. L. et al. Higher circulating expression levels of miR-221 associated with poor overall survival in renal cell carcinoma patients. Tumour Biol 35, 4057–4066 (2014).
    1. Iwamoto H. et al. Serum miR-210 as a potential biomarker of early clear cell renal cell carcinoma. Int J Oncol 44, 53–58 (2014).
    1. Pu X. X. et al. Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression. J Gastroenterol Hepatol 25, 1674–1680 (2010).
    1. Song M. Y. et al. Identification of serum microRNAs as novel non-invasive biomarkers for early detection of gastric cancer. PLoS One 7, e33608 (2012).
    1. Li Z. H. et al. Prognostic significance of serum microRNA-210 levels in nonsmall- cell lung cancer. J Int Med Res 41, 1437–1444 (2013).
    1. Cheng H. H. et al. Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia. PLoS One 8, e69239 (2013).
    1. Wu C. et al. Diagnostic and prognostic implications of a serum miRNA panel in oesophageal squamous cell carcinoma. PLoS One 9, e92292 (2014).
    1. Zanutto S. et al. Circulating miR-378 in plasma: a reliable, haemolysis-independent biomarker for colorectal cancer. Br J Cancer 110, 1001–1007 (2014).
    1. Liu H. et al. Genome-wide microRNA profiles identify miR-378 as a serum biomarker for early detection of gastric cancer. Cancer Lett 316, 196–203 (2012).
    1. Liu X. et al. Diagnostic and prognostic value of plasma microRNA deregulation in nasopharyngeal carcinoma. Cancer Biol Ther 14, 1133–1142 (2013).
    1. Chen X. et al. A combination of let-7d, let-7g and let-7i serves as a stable reference for normalization of serum microRNAs. PLoS One 8, 1–12 (2013).
    1. Zhang G. J., Zhou H., Xiao H. X., Li Y. & Zhou T. MiR-378 is an independent prognostic factor and inhibits cell growth and invasion in colorectal cancer. BMC Cancer 214, 1–9 (2014).
    1. Fei B. & Wu H. MiR-378 inhibits progression of human gastric cancer MGC-803 cells by targeting MAPK1 in vitro. Oncol Res 220, 557–564 (2012).
    1. Yu B. L. et al. MicroRNA-378 functions as an onco-miR in nasopharyngeal carcinoma by repressing TOB2 expression. Int J Oncol 44, 1215–1222 (2014).
    1. Chan J. K. et al. MiR-378 as a biomarker for response to anti-angiogenic treatment in ovarian cancer. Gynecol Oncol 133, 568–574 (2014).
    1. Xia J. T. et al. MicroRNA-362 induces cell proliferation and apoptosis resistance in gastric cancer by activation of NF-κB signaling. J Transl Med 12, 1–12 (2014).
    1. Benjamin H. et al. A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma. J Mol Diagn 12, 771–779 (2010).
    1. Almeida M. I. et al. Strand-specific miR-28-5p and miR-28-3p have distinct effects in colorectal cancer cells. Gastroenterology 142, 886–896 (2012).
    1. Li Z., Gu X., Fang Y., Xiang J. & Chen Z. microRNA expression profiles in human colorectal cancers with brain metastases. Oncol Lett 3, 346–350 (2012).
    1. Luo Y. et al. Increased serum and urinary microRNAs in children with idiopathic nephrotic syndrome. Clin Chem 59, 658–666 (2013).

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel