Virchows Archiv

, Volume 465, Issue 4, pp 463–471 | Cite as

Expression of microRNA miR-126 and miR-200c is associated with prognosis in patients with non-small cell lung cancer

  • Mi Kyeong Kim
  • Sang Bong Jung
  • Jong-Sik Kim
  • Mee Sook Roh
  • Ji Hyun Lee
  • Eun Hee Lee
  • Hyoun Wook Lee
Original Article

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that exert a critical influence on tumorigenesis through post-transcriptional modification and are considered to be potential biomarkers for the diagnosis or prognosis of various cancers. Although several miRNAs have been proposed as relevant biomarkers for non-small cell lung cancer (NSCLC), detailed working mechanisms and validated prognostic significance of these miRNAs remain controversial. In this study, we evaluated expression levels of miRNA-126 (miR-126) and miR-200c in 72 NSCLCs and 30 benign lung tissues by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and analyzed the correlation of miRNA expression with a variety of clinicopathological factors and patient survival. Compared with the benign control group, miR-126 expression was significantly downregulated in NSCLCs (p < 0.001), while miR-200c expression was significantly upregulated in NSCLCs (p < 0.001). The expression of miR-126 was significantly higher in NSCLCs with a tumor size of ≤3 cm than in those with a tumor size of >3 cm (p = 0.026). There were no other significant associations between miRNA expression and clinicopathological features. In univariate survival analysis for all NSCLC patients, high miR-200c expression (p = 0.037), large tumor size (p = 0.026), and lymphovascular invasion (p = 0.012) were significantly correlated with worse overall survival. High miR-126 expression was significantly associated with favorable prognosis only in patients with adenocarcinoma (p = 0.033). In multivariate analysis, miR-200c and tumor size remained as independent prognostic factors. Our results suggest that miR-126 might play tumor-suppressive and miR-200c an oncogenic role, and these miR’s are potential prognostic biomarkers for NSCLC.

Keywords

Non-small cell lung cancer miRNA miR-126 miR-200c Quantitative RT-PCR Prognosis 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 55:371–377Google Scholar
  2. 2.
    Spira A, Ettinger DS (2004) Multidisciplinary management of lung cancer. N Eng J Med 59:225–249Google Scholar
  3. 3.
    Eulalio A, Huntzinger E, Nishihara T, Rehwinkel J, Fauser M, Izaurralde E (2009) Deadenylation is a widespread effect of miRNA regulation. RNA 15:21–32PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Caldas C, Brenton JD (2005) Sizing up miRNAs as cancer genes. Nat Med 11:712–714PubMedCrossRefGoogle Scholar
  6. 6.
    Lagos-Quintana M, Rauhurt R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294:853–858PubMedCrossRefGoogle Scholar
  7. 7.
    Bandres E, Agirre X, Ramire N, Zarate R, Garcia-Foncillas J (2007) MicroRNAs as cancer players: potential clinical and biological effects. DNA Cell Biol 26:273–282PubMedCrossRefGoogle Scholar
  8. 8.
    Sassen S, Miska EA, Caldas C (2008) MicroRNA: implications for cancer. Virchows Arch 452:1–10PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269PubMedCrossRefGoogle Scholar
  10. 10.
    Schmidt M, Paes K, De Mazière A, Smyczek T, Yang S, Gray A, French D, Kasman I, Klumperman J, Rice DS, Ye W (2007) EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 134:2913–2923PubMedCrossRefGoogle Scholar
  11. 11.
    Sun Y, Bai Y, Zhang F, Wang Y, Guo Y, Guo L (2010) miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem Biophys Res Commun 391:1483–1489PubMedCrossRefGoogle Scholar
  12. 12.
    Crawford M, Brawner E, Batte K, Yu L, Hunter MG, Otterson GA, Nuovo G, Marsh CB, Nana-Sinkam SP (2008) MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun 373:607–612PubMedCrossRefGoogle Scholar
  13. 13.
    Liu B, Peng XC, Zheng XL, Wang J, Qin YW (2009) MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. Lung Cancer 66:169–175PubMedCrossRefGoogle Scholar
  14. 14.
    Hurteau GJ, Carlson JA, Spivack SD, Brock GJ (2007) Overexpression of the microRNA has-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res 67:7972–7976PubMedCrossRefGoogle Scholar
  15. 15.
    Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283:14910–14914PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Guarino M, Rubino B, Ballabio G (2007) The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39:305–318PubMedCrossRefGoogle Scholar
  17. 17.
    Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRefGoogle Scholar
  18. 18.
    Yang J, Lan H, Huang X, Liu B, Tong Y (2012) MicroRNA-126 inhibits tumor cell growth and its expression level correlates with poor survival in non-small cell lung cancer patients. PLoS ONE 7:e42978PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Jusufović E, Rijavec M, Keser D, Korošec P, Sodja E, Iljazović E, Radojević Z, Košnik M (2012) Let-7b and miR-126 are down-regulated in tumor tissue and correlate with microvessel density and survival outcomes in non-small-cell lung cancer. PLoS ONE 7:e45577PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Donnem T, Lonvik K, Eklo K, Berg T, Sorbye SW, Al-Shibli K, Al-Saad S, Andersen S, Stenvold H, Bremnes RM, Busund LT (2011) Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer. Cancer 117:3193–3200PubMedCrossRefGoogle Scholar
  21. 21.
    Ceppi P, Mudduluru G, Kumarswamy R, Rapa I, Scagliotti GV, Papotti M, Allgayer H (2010) Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol Cancer Res 8:1207–1216PubMedCrossRefGoogle Scholar
  22. 22.
    Liu XG, Zhu WY, Huang YY, Ma LN, Zhou SQ, Wang YK, Zeng F, Zhou JH, Zhang YK (2012) High expression of serum miR-21 and tumor miR-200c associated with poor prognosis in patients with lung cancer. Med Oncol 29:618–626PubMedCrossRefGoogle Scholar
  23. 23.
    Tsim S, O'Dowd CA, Milroy R, Davidson S (2010) Staging of non-small cell lung cancer (NSCLC): a review. Respir Med 104:1767–1774PubMedCrossRefGoogle Scholar
  24. 24.
    Võsa U, Vooder T, Kolde R, Vilo J, Metspalu A, Annilo T (2013) Meta-analysis of microRNA expression in lung cancer. Int J Cancer 132:2884–2893PubMedCrossRefGoogle Scholar
  25. 25.
    Landi MT, Zhao Y, Rotunno M, Koshiol J, Liu H, Bergen AW, Rubagotti M, Goldstein AM, Linnoila I, Marincola FM, Tucker MA, Bertazzi PA, Pesatori AC, Caporaso NE, McShane LM, Wang E (2010) MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res 16:430–441PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, Su TJ, Chiang CC, Li HN, Hong QS, Su HY, Chen CC, Chen WJ, Liu CC, Chan WK, Chen WJ, Li KC, Chen JJ, Yang PC (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13:48–57PubMedCrossRefGoogle Scholar
  27. 27.
    Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198PubMedCrossRefGoogle Scholar
  28. 28.
    Hamano R, Miyata H, Yamasaki M, Kurokawa Y, Hara J, Moon JH, Nakajima K, Takiguchi S, Fujiwara Y, Mori M, Doki Y (2011) Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway. Clin Cancer Res 17:3029–3038PubMedCrossRefGoogle Scholar
  29. 29.
    Chen J, Wang W, Zhang Y, Hu T, Chen Y (2014) The roles of miR-200c in colon cancer and associated molecular mechanisms. Tumor Biol. doi:10.1007/s13277-014-1860-x Google Scholar
  30. 30.
    Park YA, Lee JW, Choi JJ, Jeon HK, Cho Y, Choi C, Kim TJ, Lee NW, Kim BG, Bae DS (2012) The interactions between microRNA-200c and BRD7 in endometrial carcinoma. Gynecol Oncol 124:125–133PubMedCrossRefGoogle Scholar
  31. 31.
    Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Ménard S, Croce CM (2007) MicroRNA signatures in human ovarian cancer. Cancer Res 67:8699–8707PubMedCrossRefGoogle Scholar
  32. 32.
    Meng F, Henson R, Lang M, Wehbe H, Maheshwari S, Mendell JT, Jiang J, Schmittgen TD, Patel T (2006) Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology 130:2113–2129PubMedCrossRefGoogle Scholar
  33. 33.
    Kopp F, Wagner E, Roidl A (2014) The proto-oncogene KRAS is targeted by miR-200c. Oncotarget 5:185–195PubMedPubMedCentralGoogle Scholar
  34. 34.
    Tsunoda T, Takashima Y, Yoshida Y, Doi K, Tanaka Y, Fujimoto T, Machida T, Ota T, Koyanagi M, Kuroki M, Sasazuki T, Shirasawa S (2011) Oncogenic KRAS regulates miR-200c and miR-221/222 in a 3D-specific manner in colorectal cancer cells. Anticancer Res 31:2453–2460PubMedGoogle Scholar
  35. 35.
    Hu Y, Correa AM, Hoque A, Guan B, Ye F, Huang J, Swisher SG, Wu TT, Ajani JA, Xu XC (2011) Prognostic significance of differentially expressed miRNAs in esophageal cancer. Int J Cancer 128:132–143PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Mi Kyeong Kim
    • 1
  • Sang Bong Jung
    • 1
  • Jong-Sik Kim
    • 2
  • Mee Sook Roh
    • 3
  • Ji Hyun Lee
    • 4
  • Eun Hee Lee
    • 5
  • Hyoun Wook Lee
    • 5
  1. 1.Department of Clinical Laboratory ScienceGimhae CollegeGimhaeSouth Korea
  2. 2.Department of AnatomyKosin University College of MedicineBusanSouth Korea
  3. 3.Department of PathologyDong-A University College of MedicineBusanSouth Korea
  4. 4.Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Samsung Changwon HospitalSungkyunkwan University School of MedicineChangwonSouth Korea
  5. 5.Department of Pathology, Samsung Changwon HospitalSungkyunkwan University School of MedicineChangwonSouth Korea

Personalised recommendations