Abstract
Background
MicroRNAs (miRNAs) have long been established to remain stable in circulation, and dysregulated miRNAs in serum of tumor patients could potentially serve as novel biomarkers.
Aims
To determine whether certain serum miRNAs could represent potential diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC).
Methods
About 35 patients diagnosed with PDAC at different stages between August 2007 and January 2009 were enrolled in this study. Sera from 15 chronic pancreatitis (CP) patients and 15 healthy individuals were treated as controls. Quantitative real-time polymerase chain reaction assays specific to mature miRNAs were used to quantify the relative levels of those PDAC-associated serum miRNAs.
Results
Of the seven miRNAs detected, three were identified as differentially expressed in PDAC and control groups. miR-21 was able to distinguish PDAC patients from CP (p = 0.033) and healthy subjects (p = 0.001), whereas miR-155 and miR-196a were able to differentiate sera with sick pancreas (PDAC/CP) from normal pancreas (p = 0.0002 and 0.010, respectively). Serum miR-196a expression levels in unresectable PDAC (stages III and IV) patients were significantly higher than those in resectable (stages I and II) patients (p = 0.001). Furthermore, serum miR-196a expression level was found to have a potential value in predicting median survival time of PDAC patients (high-level miR-196a, 6.1 months, (95% CI, 4.49–7.72) versus low-level miR-196a, 12.00 months, (95% CI, 5.92–18.08), p = 0.007).
Conclusions
Serum miR-196a could be a potential noninvasive marker for PDAC prognosis and selection of laparotomy.
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Abbreviations
- miRNA:
-
microRNA
- PDAC:
-
Pancreatic ductal adenocarcinoma
- CP:
-
Chronic pancreatitis
- ROC:
-
Receiver operating characteristic
- TNM:
-
Tumor-node-metastasis
References
Gallagher SF, Zervos EE, Murr MM. Distal pancreatectomy. In: Von Hoff DD, Evans DB, Hruban RH, eds. Pancreatic Cancer. Boston, MA: Jones and Bartlett Publishing Company; 2005:299–312.
Yen TW, Abdalla EK, Pisters PW, Evans DB. Pancreaticoduodenectomy. In: Von Hoff DD, Evans DB, Hruban RH, eds. Pancreatic Cancer. Boston, MA: Jones and Bartlett Publishing Company; 2005:265–286.
Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging System: report from the National Cancer Database. Cancer. 2007;110:738–744.
Sener SF, Fremgen A, Menck HR, Winchester DP. Pancreatic cancer: a report of treatment and survival trends for 100, 313 patients diagnosed from 1985–1995, using the National Cancer Database. J Am Coll Surg. 1999;189:1–7.
Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. Mirbase: tools for microRNA genomics. Nucleic Acids Res. 2008;36:D154–D158.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.
Lawrie CH, Gal S, Dunlop HM, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large β-cell lymphoma. Br J Haematol. 2008;141:672–675.
Ng EK, Chong WW, Jin H, et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009;58:1375–1381.
Dillhoff M, Liu J, Frankel W, Croce C, Bloomston M. MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival. J Gastrointest Surg. 2008;12:2171–2176.
Gironella M, Seux M, Xie MJ, et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci USA. 2007;104:16170–16175.
Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–1908.
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor generation and wound healing. N Engl J Med. 1986;315:1650–1659.
Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–563.
Ji X, Takahashi R, Hiura Y, Hirokawa G, Fukushima Y, Iwai N. Plasma miR-208 as a biomarker of myocardial injury. Clin Chem. 2009;55:1944–1949.
Laterza OF, Lim L, Garrett-Engele PW, et al. Plasma microRNAs as sensitive and specific biomarkers of tissue injury. Clin Chem. 2009;55:1977–1983.
Wang K, Zhang S, Marzolf B, et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci USA. 2009;106:4402–4407.
Wang GK, Zhu JQ, Zhang JT, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31:659–666.
Tandon RK, Sato N, Garg PK. Chronic pancreatitis: Asia-Pacific consensus report. J Gastroenterol Hepatol. 2002;17:508–518.
Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–10518.
Katz MH, Hwang R, Fleming JB, Evans DB. Tumor-node-metastasis staging of pancreatic adenocarcinoma. CA Cancer J Clin. 2008;58:111–125.
Wang J, Chen J, Chang P, et al. MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res. 2009;2:807–813.
Tsui NB, Ng EK, Lo YM. Stability of endogenous and added RNA in blood specimens, serum, and plasma. Clin Chem. 2002;48:1647–1653.
Reddi KK, Holland JF. Elevated serum ribonuclease in patients with pancreatic cancer. Proc Natl Acad Sci USA. 1976;73:2308–2310.
Tanaka M, Oikawa K, Takanashi M, et al. Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS One. 2009;4:e5532.
Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One. 2008;3:e3148.
Jeyaseelan K, Lim KY, Armugam A. MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke. 2008;39:959–966.
Ma G, Guo KJ, Zhang H, et al. Expression of programmed cell death 4 and its clinicopathological significance in human pancreatic cancer. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2005;27:597–600.
Masui T, Doi R, Koshiba T, et al. RECK expression in pancreatic cancer: its correlation with lower invasiveness and better prognosis. Clin Cancer Res. 2003;9:1779–1784.
van Niel G, Porto-Carreiro I, Simoes S, Raposo G. Exosomes: a common pathway for a specialized function. J Biochem. 2006;140:13–21.
Johnstone RM. The Jeanne Manery-Fisher memorial lecture 1991. Maturation of reticulocytes: formation of exosomes as a mechanism for shedding membrane proteins. Biochem Cell Biol. 1992;70:179–190.
Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother. 2006;55:808–818.
Debernardi S, Skoulakis S, Molloy G, Chaplin T, Dixon-McIver A, Young BD. MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis. Leukemia. 2007;21:912–916.
Hu Z, Chen J, Tian T, et al. Genetic variants of miRNA sequences and non-small cell lung cancer survival. J Clin Invest. 2008;118:2600–2608.
Luthra R, Singh RR, Luthra MG, et al. MicroRNA-196a targets annexin A1: a microRNA-mediated mechanism of annexin A1 downregulation in cancers. Oncogene. 2008;27:6667–6678.
Maru DM, Singh RR, Hannah C, et al. MicroRNA-196a is a potential marker of progression during Barrett’s metaplasia-dysplasia-invasive adenocarcinoma sequence in esophagus. Am J Pathol. 2009;174:1940–1948.
Szafranska AE, Doleshal M, Edmunds HS, et al. Analysis of microRNAs in pancreatic fine-needle aspirates can classify benign and malignant tissues. Clin Chem. 2008;54:1716–1724.
Jackson DB. Serum-based microRNAs: are we blinded by potential? Proc Natl Acad Sci USA. 2009;106:E5.
Acknowledgments
All authors would like to thank Xiaofei Ye, Ph.D. from the Statistics Department of SMMU for data collection and analysis.
Funding support
The project was supported by the China Key Technology R&D Program (Grant No. 2006BAI02A12) and National Nature Science Foundation of China (30971344).
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Xiangyu Kong, Yiqi Du, and Guokun Wang are the co-first authors, and have contributed equally to this work.
An erratum to this article can be found at http://dx.doi.org/10.1007/s10620-010-1410-3
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Kong, X., Du, Y., Wang, G. et al. Detection of Differentially Expressed microRNAs in Serum of Pancreatic Ductal Adenocarcinoma Patients: miR-196a Could Be a Potential Marker for Poor Prognosis. Dig Dis Sci 56, 602–609 (2011). https://doi.org/10.1007/s10620-010-1285-3
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DOI: https://doi.org/10.1007/s10620-010-1285-3