Tumor Biology

, Volume 36, Issue 12, pp 9447–9456 | Cite as

Elevated miR-483-3p expression is an early event and indicates poor prognosis in pancreatic ductal adenocarcinoma

  • Cuiping Wang
  • Yang Sun
  • Huanwen Wu
  • Shuangni Yu
  • Li Zhang
  • Yunxiao Meng
  • Mingyang Liu
  • Haiyan Yang
  • Pingping Liu
  • Xinxin Mao
  • Zhaohui Lu
  • Jie Chen
Research Article

Abstract

MiR-483-3p has been reported to be widely involved in diverse human malignancies. However, the exact role of miR-483-3p remains elusive in pancreatic ductal adenocarcinoma (PDAC). The objective of this study is to determine the expression pattern and clinical implications of miR-483-3p in PDAC. MiR-483-3p levels were evaluated by locked nucleic acid-in situ hybridization (LNA-ISH) in a tissue microarray including 63 PDAC tumors and 10 normal pancreatic tissues, followed by evaluation in an independent set of 117 pairs of matched PDAC tumors and adjacent tumor-free pancreatic tissues. Expression of miR-483-3p was further evaluated in pancreatic intra-epithelial neoplasias (PanINs) and chronic pancreatitis (CP). The impact of miR-483-3p on cell proliferation, growth, and anchorage-independent colony formation was also assessed in vitro and in vivo. Microarray analysis revealed that miR-483-3p was positively stained in 61 (96.8 %) PDAC samples, but not detectable in normal pancreatic duct tissue. In the 117 PDAC samples, 100 % were miR-483-3p positive, with 55.6 % (65/117) strongly positive, compared to only 13.7 % (16/117) weakly positive in adjacent normal pancreatic duct tissues. MiR-483-3p expression was associated with tumor grading (p < 0.05) and was an independent predictor of poor overall survival in multivariate analysis (HR = 2.584; 95 % CI = 1.268–5.264). Moreover, from PanIN1 to PanIN3, the rate of strong miR-483-3p-positive staining was 0 % (0/39), 14.8 % (4/27), and 87.5 % (14/16), respectively. Six (54.5 %) CP samples were only weakly stained for miR-483-3p. Inhibition of miR-483-3p suppressed cell proliferation, growth, and colony formation in vitro and decreased tumor cell growth in nude mouse xenografts in vivo. These results suggest that aberrant miR-483-3p expression is an early event in PDAC tumorigenesis and is associated with tumor differentiation and prognosis. It also may be a potential target for PDAC molecular therapeutics.

Keywords

MiR-483-3p In situ hybridization Pancreatic ductal adenocarcinoma (PDAC) Pancreatic intra-epithelial neoplasia (PanIN) Chronic pancreatitis (CP) Differentiation Prognosis 

Notes

Acknowledgments

This study was supported by The National Nature Science Foundation of China (No. 30973470, No. 81172334, and No. 81400664).

Conflicts of interest

None

Supplementary material

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High resolution (TIFF 980 kb)
13277_2015_3690_MOESM2_ESM.doc (31 kb)
Table S1 (DOC 31 kb)
13277_2015_3690_MOESM3_ESM.doc (48 kb)
Table S2 (DOC 48 kb)

References

  1. 1.
    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;110:738–44.CrossRefPubMedGoogle Scholar
  2. 2.
    He Y, Zheng R, Li D, et al. Pancreatic cancer incidence and mortality patterns in China, 2011. Chin J Cancer Res. 2015;27:29–37.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas—616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4:567–79.CrossRefPubMedGoogle Scholar
  4. 4.
    Pisters PW, Wolff RA, Crane CH, Evans DB. Combined-modality treatment for operable pancreatic adenocarcinoma. Oncology (Williston Park). 2005;19:393–404. 409–10,412-6.Google Scholar
  5. 5.
    Cho WC. OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer. 2007;6:60.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ross JS, Carlson JA, Brock G. miRNA: the new gene silencer. Am J Clin Pathol. 2007;128:830–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Law PT, Wong N. Emerging roles of microRNA in the intracellular signaling networks of hepatocellular carcinoma. J Gastroenterol Hepatol. 2011;26:437–49.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhang B, Pan X, Cobb GP, Anderson TA. MicroRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.CrossRefPubMedGoogle Scholar
  9. 9.
    Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.CrossRefPubMedGoogle Scholar
  10. 10.
    Otsuka M, Kishikawa T, Yoshikawa T, et al. The role of microRNAs in hepatocarcinogenesis: current knowledge and future prospects. J Gastroenterol. 2014;49:173–84.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang V, Wu W. MicroRNA-based therapeutics for cancer. Bio Drug. 2009;23:15–23.Google Scholar
  12. 12.
    Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Sonkoly E, Wei T, Janson PC, et al. MicroRNAs: novel regulators involved in the pathogenesis of psoriasis? PLoS One. 2007;2:e610.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Joyce CE, Zhou X, Xia J, et al. Deep sequencing of small RNAs from human skin reveals major alterations in the psoriasis miRNAome. Hum Mol Genet. 2011;20:4025–40.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kong D, Piao YS, Yamashita S, et al. Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells. Oncogene. 2012;31:3949–60.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang W, Zhao LJ, Tan YX, Ren H, Qi ZT. MiR-138 induces cell cycle arrest by targeting cyclin D3 in hepatocellular carcinoma. Carcinogenesis. 2012;33:1113–20.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang W, Zhao LJ, Tan YX, Ren H, Qi ZT. Identification of deregulated miRNAs and their targets in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol. 2012;18:5442–53.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Yi C, Wang Q, Wang L, et al. MiR-663, a microRNA targeting p21 (WAF1/CIP1), promotes the proliferation and tumorigenesis of nasopharyngeal carcinoma. Oncogene. 2012;31:4421–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Veronese A, Lupini L, Consiglio J, et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res. 2010;70:3140–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Wang C, Sun Y, Wu H, et al. Distinguishing adrenal cortical carcinomas and adenomas: a study of clinicopathological features and biomarkers. Histopathology. 2014;64:567–76.CrossRefPubMedGoogle Scholar
  21. 21.
    Tang W, Zhu J, Su S, et al. MiR-27 as a prognostic marker for breast cancer progression and patient survival. PLoS One. 2012;7:e51702.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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.PubMedPubMedCentralGoogle Scholar
  23. 23.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hao J, Zhang S, Zhou Y, Hua X, Shao C. MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer. FEBS Lett. 2011;585:207–13.CrossRefPubMedGoogle Scholar
  25. 25.
    Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006;20:1218–49.CrossRefPubMedGoogle Scholar
  26. 26.
    Feldmann G, Beaty R, Hruban RH, Maitra A. Molecular genetics of pancreatic intraepithelial neoplasia. J Hepatobiliary Pancreat Surg. 2007;14:224–32.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Maitra A, Adsay NV, Argani P, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol. 2003;16:902–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Yu J, Li A, Hong SM, Hruban RH, Goggins M. MicroRNA alterations of pancreatic intraepithelial neoplasias. Clin Cancer Res. 2012;18:981–92.CrossRefPubMedGoogle Scholar
  29. 29.
    Hruban RH, Maitra A, Kern SE, Goggins M. Precursors to pancreatic cancer. Gastroenterol Clin N Am. 2007;36:831–49.CrossRefGoogle Scholar
  30. 30.
    Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology. 1995;109:247–51.CrossRefPubMedGoogle Scholar
  31. 31.
    Ekbom A, McLaughlin JK, Karlsson BM, et al. Pancreatitis and pancreatic cancer: a population-based study. J Natl Cancer Inst. 1994;86:625–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Malka D, Hammel P, Maire F, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut. 2002;51:849–52.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer: International Pancreatitis Study Group. N Engl J Med. 1993;328:1433–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Yan L, McFaul C, Howes N, et al. Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. Gastroenterology. 2005;128:2124–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Logsdon CD, Ji B. Ras activity in acinar cells links chronic pancreatitis and pancreatic cancer. Clin Gastroenterol Hepatol. 2009;7:S40–3.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Lee CS, Rush M, Charalambous D, Rode J. Immunohistochemical demonstration of the p53 tumour suppressor gene product in cancer of the pancreas and chronic pancreatitis. J Gastroenterol Hepatol. 1993;8:465–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Özata DM, Caramuta S, Velázquez-Fernández D, et al. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr Relat Cancer. 2011;18:643–55.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bertero T, Gastaldi C, Bourget-Ponzio I, et al. miR-483-3p controls proliferation in wounded epithelial cells. FASEB J. 2011;25:3092–105.CrossRefPubMedGoogle Scholar
  39. 39.
    Bertero T, Gastaldi C, Bourget-Ponzio I, et al. CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest. Cell Death Differ. 2013;20:800–11.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bertero T, Bourget-Ponzio I, Puissant A, et al. Tumor suppressor function of miR-483-3p on squamous cell carcinomas due to its pro-apoptotic properties. Cell Cycle. 2013;12:2183–93.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Jeffers JR, Parganas E, Lee Y, et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell. 2003;4:321–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19:2783–810.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Cuiping Wang
    • 1
    • 2
  • Yang Sun
    • 1
  • Huanwen Wu
    • 1
  • Shuangni Yu
    • 1
  • Li Zhang
    • 1
  • Yunxiao Meng
    • 1
  • Mingyang Liu
    • 1
  • Haiyan Yang
    • 1
  • Pingping Liu
    • 1
  • Xinxin Mao
    • 1
  • Zhaohui Lu
    • 1
  • Jie Chen
    • 1
  1. 1.Department of Pathology, Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.Department of Pathology, Beijing Tsinghua Changgung Hospital, Medical CenterTsinghua UniversityBeijingChina

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