Annals of Surgical Oncology

, Volume 17, Issue 12, pp 3120–3128 | Cite as

MicroRNA-203 Expression as a New Prognostic Marker of Pancreatic Adenocarcinoma

  • Naoki Ikenaga
  • Kenoki Ohuchida
  • Kazuhiro Mizumoto
  • Jun Yu
  • Tadashi Kayashima
  • Hiroshi Sakai
  • Hayato Fujita
  • Kohei Nakata
  • Masao Tanaka
Pancreatic Tumors



Detection of aberrant microRNA (miR) expression may contribute to diagnosis and prognosis of various cancers. The aim of this study is to evaluate the correlation between miR-203 expression and prognosis of patients with pancreatic adenocarcinoma after curative resection.


A total of 113 formalin-fixed paraffin-embedded tissue samples of pancreatic adenocarcinoma, 20 samples of chronic pancreatitis, and 8 samples of normal pancreas were obtained. We investigated the association of miR-203 expression measured by quantitative reverse-transcription polymerase chain reaction assays with clinicopathological parameters and survival times.


miR-203 was overexpressed in pancreatic adenocarcinoma samples compared with chronic pancreatitis (P < 0.001) and normal pancreas (P = 0.001) samples. An association between miR-203 expression and clinicopathological factors of pancreatic adenocarcinoma was not observed. On univariate analysis, the high-miR-203 group and the subgroup (20%) of cases with the highest miR-203 overexpression had significantly shorter survival time (P = 0.048 and P = 0.024, respectively). Multivariate analysis revealed that miR-203 expression was an independent predictor of poor prognosis in cases with no residual tumor (relative risk 2.298, P = 0.027).


miR-203 expression is a new prognostic marker in pancreatic adenocarcinoma patients.


Chronic Pancreatitis Pancreatic Adenocarcinoma Pancreatic Cancer Cell Line Normal Pancreas FFPE Sample 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants from the Takeda Science Foundation, Pancreas Research Foundation of Japan, and Nakajima Foundation.

Supplementary material

10434_2010_1188_MOESM1_ESM.doc (34 kb)
Supplementary material 1 (DOC 33 kb)


  1. 1.
    Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  3. 3.
    Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–6.CrossRefPubMedGoogle Scholar
  4. 4.
    He L, Thomson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.CrossRefPubMedGoogle Scholar
  5. 5.
    O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435:839–43.CrossRefPubMedGoogle Scholar
  6. 6.
    Calin GA, Trapasso F, Shimizu M, et al. Familial cancer associated with a polymorphism in ARLTS1. N Engl J Med. 2005;352:1667–76.CrossRefPubMedGoogle Scholar
  7. 7.
    Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.CrossRefPubMedGoogle Scholar
  8. 8.
    Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Iorio MV, Ferracin M, Liu CG, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065–70.CrossRefPubMedGoogle Scholar
  10. 10.
    Yanaihara N, Caplen N, Bowman E, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189–98.CrossRefPubMedGoogle Scholar
  11. 11.
    Yeo TP, Hruban RH, Leach SD, et al. Pancreatic cancer. Curr Probl Cancer. 2002;26:176–275.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Buchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91:586–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg. 2006;244:10–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP. Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer. 2005;41:2213–36.CrossRefPubMedGoogle Scholar
  16. 16.
    Sinicrope FA, Evans DB, Leach SD, Cleary KR, Fenoglio CJ, Lee JJ, et al. bcl-2 and p53 expression in resectable pancreatic adenocarcinomas: association with clinical outcome. Clin Cancer Res. 1996;2:2015–22.PubMedGoogle Scholar
  17. 17.
    Friess H, Lu Z, Andren-Sandberg A, et al. Moderate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer. Ann Surg. 1998;228:780–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Nio Y, Dong M, Iguchi C, Yamasawa K, Toga T, Itakura M, et al. Expression of Bcl-2 and p53 protein in resectable invasive ductal carcinoma of the pancreas: effects on clinical outcome and efficacy of adjuvant chemotherapy. J Surg Oncol. 2001;76:188–96.CrossRefPubMedGoogle Scholar
  19. 19.
    Yamamoto H, Itoh F, Iku S, et al. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human pancreatic adenocarcinomas: clinicopathologic and prognostic significance of matrilysin expression. J Clin Oncol. 2001;19:1118–27.PubMedGoogle Scholar
  20. 20.
    Joo YE, Rew JS, Park CS, Kim SJ. Expression of E-cadherin, alpha- and beta-catenins in patients with pancreatic adenocarcinoma. Pancreatology. 2002;2:129–37.CrossRefPubMedGoogle Scholar
  21. 21.
    Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer. 2000;88:2239–45.CrossRefPubMedGoogle Scholar
  22. 22.
    Niedergethmann M, Hildenbrand R, Wostbrock B, Hartel M, Sturm JW, Richter A, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas. 2002;25:122–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Giovannetti E, Del Tacca M, Mey V, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006;66:3928–35.CrossRefPubMedGoogle Scholar
  24. 24.
    Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q, et al. Profiling of 95 MicroRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg. 2009;33:698–709.CrossRefPubMedGoogle Scholar
  26. 26.
    Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26:4442–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Sonkoly E, Wei T, Janson PC, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS ONE. 2007;2:e610.CrossRefGoogle Scholar
  28. 28.
    Yi R, Poy MN, Stoffel M, Fuchs E. A skin microRNA promotes differentiation by repressing ‘stemness’. Nature. 2008;452:225–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Lena AM, Shalom-Feuerstein R, di Val Cervo PR, Aberdam D, Knight RA, Melino G, et al. miR-203 represses ‘stemness’ by repressing DeltaNp63. Cell Death Differ. 2008;15:1187–95.CrossRefPubMedGoogle Scholar
  30. 30.
    Bueno MJ, Perez de Castro I, Gomez de Cedron M, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell. 2008;13:496–506.CrossRefPubMedGoogle Scholar
  31. 31.
    Bachem MG, Schneider E, Gross H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421–32.CrossRefPubMedGoogle Scholar
  32. 32.
    Hamilton SR, Aaltonen LA (editors): World Health Organization Classification of Tumours. Pathology and genetics of tumours of the digestive system. IARC: Lyon; 2000.Google Scholar
  33. 33.
    Sobin L, Wittekind C. Union Internationale Contre le Cancer and the American Joint Committee on Cancer: TNM Classification of Malignant Tumors, 6th edition, New York: Wiley-Liss; 2002.Google Scholar
  34. 34.
    Hoffmann AC, Mori R, Vallbohmer D, et al. High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia. 2008;10:674–9.PubMedGoogle Scholar
  35. 35.
    Schetter AJ, Leung SY, Sohn JJ, et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 2008;299:425–36.CrossRefPubMedGoogle Scholar
  36. 36.
    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;12:2171–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Abrahamsen HN, Steiniche T, Nexo E, Hamilton-Dutoit SJ, Sorensen BS. Towards quantitative mRNA analysis in paraffin-embedded tissues using real-time reverse transcriptase-polymerase chain reaction: a methodological study on lymph nodes from melanoma patients. J Mol Diagn. 2003;5:34–41.PubMedGoogle Scholar
  38. 38.
    Cronin M, Pho M, Dutta D, et al. Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. Am J Pathol. 2004;164:35–42.PubMedGoogle Scholar
  39. 39.
    Farragher SM, Tanney A, Kennedy RD, Paul Harkin D. RNA expression analysis from formalin fixed paraffin embedded tissues. Histochem Cell Biol. 2008;130:435–45.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2010

Authors and Affiliations

  • Naoki Ikenaga
    • 1
  • Kenoki Ohuchida
    • 1
    • 2
  • Kazuhiro Mizumoto
    • 1
    • 3
  • Jun Yu
    • 1
  • Tadashi Kayashima
    • 1
  • Hiroshi Sakai
    • 1
  • Hayato Fujita
    • 1
  • Kohei Nakata
    • 1
  • Masao Tanaka
    • 1
  1. 1.Departments of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Departments of Advanced Medical Initiatives, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  3. 3.Kyushu University Hospital Cancer CenterFukuokaJapan

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