Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known for its very poor overall prognosis. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. We used 377 feature microRNA (miRNA) arrays to investigate miRNA expression in normal pancreas, chronic pancreatitis, and PDAC tissues as well as PDAC-derived cell lines. A pancreatic miRNome was established comparing the data from normal pancreas with a reference set of 33 human tissues. The expression of miR-216 and -217 and lack of expression of miR-133a were identified as characteristic of pancreas tissue. Unsupervised clustering showed that the three pancreatic tissues types can be classified according to their respective miRNA expression profiles. We identified 26 miRNAs most prominently misregulated in PDAC and a relative quantitative reverse transcriptase-polymerase chain reaction index using only miR-217 and -196a was found to discriminate normal pancreas, chronic pancreatitis and cancerous tissues, establishing a potential utility for miRNAs in diagnostic procedures. Lastly, comparing differentially expressed genes from PDAC with predicted miRNA target genes for the top 26 miRNAs, we identified potential novel links between aberrant miRNA expression and known target genes relevant to PDAC biology. Our data provides novel insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development and offers new candidate targets to be exploited both for diagnostic and therapeutic strategies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Al-Aynati MM, Radulovich N, Riddell RH, Tsao MS . (2004). Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia. Clin Cancer Res 10: 1235–1240.
Altomare DA, Tanno S, De Rienzo A, Klein-Szanto AJ, Skele KL, Hoffman JP et al. (2003). Frequent activation of AKT2 kinase in human pancreatic carcinomas. J Cell Biochem 88: 470–476.
Baskerville S, Bartel DP . (2005). Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 11: 241–247.
Benjamini Y, Hochberg Y . (1995). Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc 57: 289–300.
Buchholz M, Braun M, Heidenblut A, Kestler HA, Kloppel G, Schmiegel W et al. (2005). Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions. Oncogene 24: 6626–6636.
Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al. (2005). A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353: 1793–1801.
Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G et al. (2005). Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334: 1351–1358.
Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N et al. (2006). Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymp. Proc Natl Acad Sci USA 103: 7024–7029.
Davison TS, Johnson CD, Andruss BF . (2006). Analyzing micro-RNA expression using microarrays. Methods Enzymol 411: 14–34.
Dessimoz J, Bonnard C, Huelsken J, Grapin-Botton A . (2005). Pancreas-specific deletion of beta-catenin reveals Wnt-dependent and Wnt-independent functions during development. Curr Biol 15: 1677–1683.
Esquela-Kerscher A, Slack FJ . (2006). Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6: 259–269.
Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F et al. (2005). MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 102: 18081–18086.
He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S et al. (2005a). The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 102: 19075–19080.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S et al. (2005b). A microRNA polycistron as a potential human oncogene. Nature 435: 828–833.
Heidenblut AM, Luttges J, Buchholz M, Heinitz C, Emmersen J, Nielsen KL et al. (2004). aRNA-longSAGE: a new approach to generate SAGE libraries from microdissected cells. Nucleic Acids Res 32: e131.
Heiser PW, Lau J, Taketo MM, Herrera PL, Hebrok M . (2006). Stabilization of beta-catenin impacts pancreas growth. Development 133: 2023–2032.
Hornstein E, Mansfield JH, Yekta S, Hu JK-H, Harfe BD, McManus MT et al. (2005). The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature 438: 671–674.
Hu YX, Watanabe H, Li P, Wang Y, Ohtsubo K, Yamaguchi Y et al. (2000). An immunohistochemical analysis of p27 expression in human pancreatic carcinomas. Pancreas 21: 226–230.
Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M . (2002). Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18 (Suppl 1): S96–S104.
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S et al. (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65: 7065–7070.
Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M et al. (2005). Silencing of microRNAs in vivo with/‘antagomirs/’. Nature 438: 685–689.
Liu CG, Calin GA, Meloon B, Gamliel N, Sevignani C, Ferracin M et al. (2004). An oligonucleotide microchip for genome-wide microRNA profiling in human and mouse tissues. Proc Natl Acad Sci USA 101: 9740–9744.
Lu CD, Morita S, Ishibashi T, Hara H, Isozaki H, Tanigawa N . (1999). Loss of p27Kip1 expression independently predicts poor prognosis for patients with resectable pancreatic adenocarcinoma. Cancer 85: 1250–1260.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. (2005). MicroRNA expression profiles classify human cancers. Nature 435: 834–838.
Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE et al. (2004). A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432: 226–230.
Prasad NB, Biankin AV, Fukushima N, Maitra A, Dhara S, Elkahloun AG et al. (2005). Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 65: 1619–1626.
Schlieman MG, Fahy BN, Ramsamooj R, Beckett L, Bold RJ . (2003). Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br J Cancer 89: 2110–2115.
Segara D, Biankin AV, Kench JG, Langusch CC, Dawson AC, Skalicky DA et al. (2005). Expression of HOXB2, a retinoic acid signaling target in pancreatic cancer and pancreatic intraepithelial neoplasia. Clin Cancer Res 11: 3587–3596.
Sevignani C, Calin GA, Siracusa LD, Croce CM . (2006). Mammalian microRNAs: a small world for fine-tuning gene expression. Mamm Genome 17: 189–202.
Shingara J, Keiger K, Shelton J, Laosinchai-Wolf W, Powers P, Conrad R et al. (2005). An optimized isolation and labeling platform for accurate microRNA expression profiling. RNA 11: 1461–1470.
Sood P, Krek A, Zavolan M, Macino G, Rajewsky N . (2006). Cell-type-specific signatures of microRNAs on target mRNA expression. Proc Natl Acad Sci USA 103: 2746–2751.
Taganov KD, Boldin MP, Chang K-J, Baltimore D . (2006). NF-{kappa}B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103: 12481–12486.
Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R . (2006). Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20: 515–524.
Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F et al. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103: 2257–2261.
Weber F, Teresi RE, Broelsch CE, Frilling A, Eng C . (2006). A limited set of human microRNA is deregulated in follicular thyroid carcinoma. J Clin Endocrinol Metab 91: 3584–3591.
Yekta S, Shih I-H, Bartel DP . (2004). MicroRNA-directed cleavage of HOXB8 mRNA. Science 304: 594–596.
Yeo T, Hruban R, Leach S, Wilentz R, Sohn T, Kern S et al. (2002). Pancreatic cancer. Curr Prob Cancer 26: 176–275.
Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A et al. (2006). Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 8: 279–289.
Acknowledgements
We thank Bernard Andruss for critical review of the manuscript and Matthias Becker for his excellent technical assistance. This work was supported in part by the Deutsche Krebshilfe (BS and SAH, 70-2988).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Supplementary information
Rights and permissions
About this article
Cite this article
Szafranska, A., Davison, T., John, J. et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26, 4442–4452 (2007). https://doi.org/10.1038/sj.onc.1210228
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210228
Keywords
This article is cited by
-
Small RNA sequencing analysis of peptide-affinity isolated plasma extracellular vesicles distinguishes pancreatic cancer patients from non-affected individuals
Scientific Reports (2023)
-
A one-pot isothermal Cas12-based assay for the sensitive detection of microRNAs
Nature Biomedical Engineering (2023)
-
Construction of Lentiviral Vector for miR-217 Overexpression and Knockdown and Its Effect on CML
Molecular Biotechnology (2023)
-
The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis
Journal of Physiology and Biochemistry (2023)
-
Circulating MicroRNAs as Noninvasive Diagnostic and Prognostic Biomarkers in Pancreatic Cancer: A Review
Journal of Gastrointestinal Cancer (2023)