Home Enhanced miR-182 transcription is a predictor of poor overall survival in colorectal adenocarcinoma patients
Article
Licensed
Unlicensed Requires Authentication

Enhanced miR-182 transcription is a predictor of poor overall survival in colorectal adenocarcinoma patients

  • Stamatia-Maria Rapti , Christos K. Kontos , Iordanis N. Papadopoulos and Andreas Scorilas EMAIL logo
Published/Copyright: March 8, 2014
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 52 Issue 8

Abstract

Background: Colorectal cancer is the second most frequent cause of cancer-related death in the developed world. Recent studies have tried to associate colorectal cancer with the aberrant expression of several microRNAs. The aim of the present study was the development of a highly sensitive quantitative real-time PCR which can be used to evaluate the miR-182 expression levels in colorectal adenocarcinoma and adjacent non-cancerous tissue specimens and associate them with several clinicopathological characteristics, aiming to examine the prognostic potential of miR-182.

Methods: Total RNA was isolated from 116 malignant colorectal adenocarcinoma specimens and 60 paired non-cancerous tissues. Then, polyadenylation of 2 μg total RNA by poly(A) polymerase and reverse transcription with suitable oligo-dT-adapter followed. miR-182 levels were quantified by real-time PCR based on SYBR Green chemistry. The results were analyzed by the comparative quantification cycle method and by extensive biostatistical analysis.

Results: miR-182 was found to be significantly upregulated in colorectal adenocarcinoma specimens compared to their non-cancerous counterparts (p<0.001). miR-182 expression increases as the histological grade increases (p=0.013). miR-182 overexpression is associated with high depth of tumor invasion, positive regional lymph node status, and advanced TNM stage of patients. Therefore, miR-182 is an unfavorable prognostic marker in colorectal adenocarcinoma, predicting poor overall survival (p=0.007). Most importantly, miR-182 expression retained its unfavorable prognostic significance among patients with well- or moderately differentiated colorectal adenocarcinoma (p=0.006) and among metastasis-free patients (p=0.025).

Conclusions: The increased levels of the oncogene-like miR-182 increase the risk for disease progression and predict poor overall survival for colorectal adenocarcinoma patients.

Keywords: colorectal cancer; microRNAs (miRNAs); molecular tumor markers; prognostic biomarkers; quantitative real-time PCR (qPCR)
Corresponding author: Andreas Scorilas, Department of Biochemistry and Molecular Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece, Phone: +30 2107274306, Fax: +30 2107274158, E-mail:

References

1. Boyle P, Levin B. Colorectal cancer. In: World cancer report. Lyon: International Agency for Research on Cancer, 2008; 374–8.Search in Google Scholar

2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917.10.1002/ijc.25516Search in Google Scholar PubMed

3. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007;18:581–92.10.1093/annonc/mdl498Search in Google Scholar PubMed

4. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96.10.3322/CA.2007.0010Search in Google Scholar PubMed

5. Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006;15:R17–29.10.1093/hmg/ddl046Search in Google Scholar PubMed

6. Laurent LC, Chen J, Ulitsky I, Mueller FJ, Lu C, Shamir R, et al. Comprehensive microRNA profiling reveals a unique human embryonic stem cell signature dominated by a single seed sequence. Stem Cells 2008;26:1506–16.10.1634/stemcells.2007-1081Search in Google Scholar PubMed

7. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004;101:2999–3004.10.1073/pnas.0307323101Search in Google Scholar PubMed PubMed Central

8. Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA. MicroRNAs – the micro steering wheel of tumour metastases. Nat Rev Cancer 2009;9:293–302.10.1038/nrc2619Search in Google Scholar PubMed

9. Lujambio A, Lowe SW. The microcosmos of cancer. Nature 2012;482:347–55.10.1038/nature10888Search in Google Scholar PubMed PubMed Central

10. Rossi S, Di Narzo AF, Mestdagh P, Jacobs B, Bosman FT, Gustavsson B, et al. microRNAs in colon cancer: a roadmap for discovery. FEBS Lett 2012;586:3000–7.10.1016/j.febslet.2012.07.048Search in Google Scholar PubMed

11. Liu Z, Liu J, Segura MF, Shao C, Lee P, Gong Y, et al. MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma. J Pathol 2012;228:204–15.10.1002/path.4000Search in Google Scholar PubMed

12. Giricz O, Reynolds PA, Ramnauth A, Liu C, Wang T, Stead L, et al. Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity. J Pathol 2012;226:108–19.10.1002/path.2978Search in Google Scholar PubMed

13. Segura MF, Hanniford D, Menendez S, Reavie L, Zou X, Alvarez-Diaz S, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci USA 2009;106:1814–9.10.1073/pnas.0808263106Search in Google Scholar PubMed PubMed Central

14. Wang J, Li J, Shen J, Wang C, Yang L, Zhang X. MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma. BMC Cancer 2012;12:227.10.1186/1471-2407-12-227Search in Google Scholar PubMed PubMed Central

15. Kong WQ, Bai R, Liu T, Cai CL, Liu M, Li X, et al. MicroRNA-182 targets cAMP-responsive element-binding protein 1 and suppresses cell growth in human gastric adenocarcinoma. FEBS J 2012;279:1252–60.10.1111/j.1742-4658.2012.08519.xSearch in Google Scholar PubMed

16. Sun Y, Fang R, Li C, Li L, Li F, Ye X, et al. Hsa-mir-182 suppresses lung tumorigenesis through down regulation of RGS17 expression in vitro. Biochem Biophys Res Commun 2010;396:501–7.10.1016/j.bbrc.2010.04.127Search in Google Scholar PubMed

17. Pignot G, Cizeron-Clairac G, Vacher S, Susini A, Tozlu S, Vieillefond A, et al. microRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer. Int J Cancer 2013;132:2479–91.10.1002/ijc.27949Search in Google Scholar PubMed

18. Siva AC, Nelson LJ, Fleischer CL, Majlessi M, Becker MM, Vessella RL, et al. Molecular assays for the detection of microRNAs in prostate cancer. Mol Cancer 2009;8:17.10.1186/1476-4598-8-17Search in Google Scholar PubMed PubMed Central

19. Zhang QH, Sun HM, Zheng RZ, Li YC, Zhang Q, Cheng P, et al. Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. Gene 2013;527:26–32.10.1016/j.gene.2013.06.006Search in Google Scholar PubMed

20. Liu H, Du L, Wen Z, Yang Y, Li J, Wang L, et al. Up-regulation of miR-182 expression in colorectal cancer tissues and its prognostic value. Int J Colorectal Dis 2013;28:697–703.10.1007/s00384-013-1674-0Search in Google Scholar PubMed

21. Cekaite L, Rantala JK, Bruun J, Guriby M, Agesen TH, Danielsen SA, et al. MiR-9, -31, and -182 deregulation promote proliferation and tumor cell survival in colon cancer. Neoplasia 2012;14:868–79.10.1593/neo.121094Search in Google Scholar PubMed PubMed Central

22. Vergoulis T, Vlachos IS, Alexiou P, Georgakilas G, Maragkakis M, Reczko M, et al. TarBase 6.0: capturing the exponential growth of miRNA targets with experimental support. Nucleic Acids Res 2012;40:D222–9.10.1093/nar/gkr1161Search in Google Scholar PubMed PubMed Central

23. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 2007;7:847–59.10.1038/nrc2223Search in Google Scholar PubMed

24. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007;128:309–23.10.1016/j.cell.2006.12.029Search in Google Scholar PubMed PubMed Central

25. Yan D, Dong XD, Chen X, Yao S, Wang L, Wang J, et al. Role of microRNA-182 in posterior uveal melanoma: regulation of tumor development through MITF, BCL2 and cyclin D2. PLoS One 2012;7:e40967.10.1371/journal.pone.0040967Search in Google Scholar PubMed PubMed Central

26. Liu R, Li J, Teng Z, Zhang Z, Xu Y. Overexpressed microRNA-182 promotes proliferation and invasion in prostate cancer PC-3 cells by down-regulating N-myc downstream regulated gene 1 (NDRG1). PLoS One 2013;8:e68982.10.1371/journal.pone.0068982Search in Google Scholar PubMed PubMed Central

27. Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS, 2nd, et al. NDRG1 is necessary for p53-dependent apoptosis. J Biol Chem 2004;279:48930–40.10.1074/jbc.M400386200Search in Google Scholar PubMed

28. Fang M, Shen Z, Huang S, Zhao L, Chen S, Mak TW, et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 2010;143:711–24.10.1016/j.cell.2010.10.010Search in Google Scholar PubMed

29. Pizzini S, Bisognin A, Mandruzzato S, Biasiolo M, Facciolli A, Perilli L, et al. Impact of microRNAs on regulatory networks and pathways in human colorectal carcinogenesis and development of metastasis. BMC Genomics 2013;14:589.10.1186/1471-2164-14-589Search in Google Scholar PubMed PubMed Central

30. Mikula M, Rubel T, Karczmarski J, Goryca K, Dadlez M, Ostrowski J. Integrating proteomic and transcriptomic high-throughput surveys for search of new biomarkers of colon tumors. Funct Integr Genomics 2010 Nov 9. [Epub ahead of print].10.1007/s10142-010-0200-5Search in Google Scholar PubMed

31. Shi R, Chiang VL. Facile means for quantifying microRNA expression by real-time PCR. Biotechniques 2005;39:519–25.10.2144/000112010Search in Google Scholar PubMed

32. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402–8.10.1006/meth.2001.1262Search in Google Scholar PubMed

33. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 2008;3:1101–8.10.1038/nprot.2008.73Search in Google Scholar PubMed

34. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 2004;10: 7252–9.10.1158/1078-0432.CCR-04-0713Search in Google Scholar PubMed

35. Nagtegaal ID, Quirke P, Schmoll HJ. Has the new TNM classification for colorectal cancer improved care? Nat Rev Clin Oncol 2012;9:119–23.10.1038/nrclinonc.2011.157Search in Google Scholar PubMed

36. Pierce ML, Weston MD, Fritzsch B, Gabel HW, Ruvkun G, Soukup GA. MicroRNA-183 family conservation and ciliated neurosensory organ expression. Evol Dev 2008;10:106–13.10.1111/j.1525-142X.2007.00217.xSearch in Google Scholar PubMed PubMed Central

37. Abraham D, Jackson N, Gundara JS, Zhao J, Gill AJ, Delbridge L, et al. MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis, prognosis, and potential therapeutic targets. Clin Cancer Res 2011;17:4772–81.10.1158/1078-0432.CCR-11-0242Search in Google Scholar PubMed

38. Lin S, Sun JG, Wu JB, Long HX, Zhu CH, Xiang T, et al. Aberrant microRNAs expression in CD133(+)/CD326(+) human lung adenocarcinoma initiating cells from A549. Mol Cells 2012;33:277–83.10.1007/s10059-012-2252-ySearch in Google Scholar PubMed PubMed Central

39. Xu X, Dong Z, Li Y, Yang Y, Yuan Z, Qu X, et al. The upregulation of signal transducer and activator of transcription 5-dependent microRNA-182 and microRNA-96 promotes ovarian cancer cell proliferation by targeting forkhead box O3 upon leptin stimulation. Int J Biochem Cell Biol 2013;45:536–45.10.1016/j.biocel.2012.12.010Search in Google Scholar PubMed

40. Tsuchiyama K, Ito H, Taga M, Naganuma S, Oshinoya Y, Nagano K, et al. Expression of microRNAs associated with Gleason grading system in prostate cancer: miR-182-5p is a useful marker for high grade prostate cancer. Prostate 2013;73:827–34.10.1002/pros.22626Search in Google Scholar PubMed

41. Hannafon BN, Sebastiani P, de las Morenas A, Lu J, Rosenberg CL. Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer. Breast Cancer Res 2011;13:R24.10.1186/bcr2839Search in Google Scholar PubMed PubMed Central

42. Yu J, Li A, Hong SM, Hruban RH, Goggins M. MicroRNA alterations of pancreatic intraepithelial neoplasias. Clin Cancer Res 2012;18:981–92.10.1158/1078-0432.CCR-11-2347Search in Google Scholar PubMed PubMed Central

43. Piepoli A, Tavano F, Copetti M, Mazza T, Palumbo O, Panza A, et al. MiRNA expression profiles identify drivers in colorectal and pancreatic cancers. PLoS One 2012;7:e33663.10.1371/journal.pone.0033663Search in Google Scholar PubMed PubMed Central

44. Sarver AL, French AJ, Borralho PM, Thayanithy V, Oberg AL, Silverstein KA, et al. Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states. BMC Cancer 2009;9:401.10.1186/1471-2407-9-401Search in Google Scholar PubMed PubMed Central

45. Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X. Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer 2010;127:118–26.10.1002/ijc.25007Search in Google Scholar PubMed

46. Peltier HJ, Latham GJ. Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. RNA 2008;14:844–52.10.1261/rna.939908Search in Google Scholar PubMed PubMed Central

47. Formisano-Treziny C, de San Feliciano M, Gabert J. Development of plasmid calibrators for absolute quantification of miRNAs by using real-time qPCR. J Mol Diagn 2012;14:314–21.10.1016/j.jmoldx.2012.02.008Search in Google Scholar PubMed

Received: 2013-11-3
Accepted: 2014-2-11
Published Online: 2014-3-8
Published in Print: 2014-8-1

©2014 by Walter de Gruyter Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Colorectal cancer and screening programs: not only analytical issues
  4. Reviews
  5. Laboratory diagnostics of inherited platelet disorders
  6. Reticulated platelets: analytical aspects and clinical utility
  7. Genetics and Molecular Diagnostics
  8. Advanced tools for BRCA1/2 mutational screening: comparison between two methods for large genomic rearrangements (LGRs) detection
  9. General Clinical Chemistry and Laboratory Medicine
  10. Establishing, harmonizing and analyzing critical values in a large academic health center
  11. Standardization of DiaSorin and Roche automated third generation PTH assays with an International Standard: impact on clinical populations
  12. First fully automated immunoassay for anti-Müllerian hormone
  13. A multicenter evaluation of dysthyroxinemia in a defined patient cohort
  14. New biomarkers in diagnosis of early onset preeclampsia and imminent delivery prognosis
  15. Soluble Fms-like tyrosine kinase-1 to placental growth factor ratio in mid-pregnancy as a predictor of preterm preeclampsia in asymptomatic pregnant women
  16. Development of a new immunoassay for the detection of ethyl glucuronide (EtG) in meconium: validation with authentic specimens analyzed using LC-MS/MS. Preliminary results
  17. Optimizing centrifugation of coagulation samples in laboratory automation
  18. Evaluation of the automated coagulation analyzer CS-5100 and its utility in high throughput laboratories
  19. A new sampling device for faecal immunochemical testing: haemoglobin stability is still an open issue
  20. Reference Values
  21. Faecal haemoglobin concentrations vary with sex and age, but data are not transferable across geography for colorectal cancer screening
  22. Cancer Diagnostics
  23. Enhanced miR-182 transcription is a predictor of poor overall survival in colorectal adenocarcinoma patients
  24. Importance of promoter methylation of GATA4 and TP53 genes in endometrioid carcinoma of endometrium
  25. Frequent methylation of HOXA9 gene in tumor tissues and plasma samples from human hepatocellular carcinomas
  26. Letters to the Editor
  27. Further comments on “Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation”
  28. A questionnaire study among nurses: awareness of blood and urine sample collection procedures
  29. Measurement uncertainty and clinical interpretation of measurement results
  30. Laboratory automation: how will you select the boarding assays?
  31. Improvement and evaluation of a 1,2-dioleoylglycerol method for measuring pancreatic lipase catalytic activity in serum
  32. The novel variant p.Ser465Leu in the PCSK9 gene does not account for the decreased LDLR activity in members of a FH family
  33. 1,5 Anhydroglucitol serum concentration as a biomarker for screening gestational diabetes in early pregnancy
  34. A rare condition: IgE type monoclonal gammopathy of undetermined significance
  35. Laboratory analysis of intraosseous blood: bad to the bone?
https://doi.org/10.1515/cclm-2013-0950
Keywords for this article
colorectal cancer; microRNAs (miRNAs); molecular tumor markers; prognostic biomarkers; quantitative real-time PCR (qPCR)

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Colorectal cancer and screening programs: not only analytical issues
  4. Reviews
  5. Laboratory diagnostics of inherited platelet disorders
  6. Reticulated platelets: analytical aspects and clinical utility
  7. Genetics and Molecular Diagnostics
  8. Advanced tools for BRCA1/2 mutational screening: comparison between two methods for large genomic rearrangements (LGRs) detection
  9. General Clinical Chemistry and Laboratory Medicine
  10. Establishing, harmonizing and analyzing critical values in a large academic health center
  11. Standardization of DiaSorin and Roche automated third generation PTH assays with an International Standard: impact on clinical populations
  12. First fully automated immunoassay for anti-Müllerian hormone
  13. A multicenter evaluation of dysthyroxinemia in a defined patient cohort
  14. New biomarkers in diagnosis of early onset preeclampsia and imminent delivery prognosis
  15. Soluble Fms-like tyrosine kinase-1 to placental growth factor ratio in mid-pregnancy as a predictor of preterm preeclampsia in asymptomatic pregnant women
  16. Development of a new immunoassay for the detection of ethyl glucuronide (EtG) in meconium: validation with authentic specimens analyzed using LC-MS/MS. Preliminary results
  17. Optimizing centrifugation of coagulation samples in laboratory automation
  18. Evaluation of the automated coagulation analyzer CS-5100 and its utility in high throughput laboratories
  19. A new sampling device for faecal immunochemical testing: haemoglobin stability is still an open issue
  20. Reference Values
  21. Faecal haemoglobin concentrations vary with sex and age, but data are not transferable across geography for colorectal cancer screening
  22. Cancer Diagnostics
  23. Enhanced miR-182 transcription is a predictor of poor overall survival in colorectal adenocarcinoma patients
  24. Importance of promoter methylation of GATA4 and TP53 genes in endometrioid carcinoma of endometrium
  25. Frequent methylation of HOXA9 gene in tumor tissues and plasma samples from human hepatocellular carcinomas
  26. Letters to the Editor
  27. Further comments on “Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation”
  28. A questionnaire study among nurses: awareness of blood and urine sample collection procedures
  29. Measurement uncertainty and clinical interpretation of measurement results
  30. Laboratory automation: how will you select the boarding assays?
  31. Improvement and evaluation of a 1,2-dioleoylglycerol method for measuring pancreatic lipase catalytic activity in serum
  32. The novel variant p.Ser465Leu in the PCSK9 gene does not account for the decreased LDLR activity in members of a FH family
  33. 1,5 Anhydroglucitol serum concentration as a biomarker for screening gestational diabetes in early pregnancy
  34. A rare condition: IgE type monoclonal gammopathy of undetermined significance
  35. Laboratory analysis of intraosseous blood: bad to the bone?
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 10.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/cclm-2013-0950/html
Scroll to top button