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Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer

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Abstract

microRNA (miR)-138 has been recognized as a potential tumor suppressor via regulating 3-phosphoinositide-dependent protein kinase-1 (PDK1) expression in non-small cell lung cancer (NSCLC) cells. The aim of this study was to investigate miR-138 and PDK1 mRNA expression in serum of NSCLC and their associations with patients’ prognosis. miR-138 and PDK1 mRNA expressions in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR. miR-138 expression level was significantly lower in NSCLC serum samples than in healthy control serum samples (P < 0.001), while PDK1 mRNA expression level was significantly increased in NSCLC serum samples compared to healthy control serum samples (P < 0.001). In addition, miR-138 downregulation and PDK1 upregulation were both significantly associated with advanced tumor-node-metastasis (TNM) stage (both P = 0.002) and positive lymph node metastasis (both P = 0.01) of NSCLC patients. Moreover, the overall survival of NSCLC patients with low miR-138 expression or high PDK1 mRNA expression was obviously shorter than those with high miR-138 expression or low PDK1 mRNA expression (both P < 0.001). Notably, NSCLC patients with combined miR-138 downregulation and PDK1 upregulation (miR-138-low/PDK1-high) had shortest overall survival (P < 0.001). Furthermore, multivariate analysis showed that miR-138 expression (P = 0.01), PDK1 expression (P = 0.01), and combined expression of miR-138 and PDK1 (miR-138/PDK1, P = 0.001) were all independent prognostic factors for overall survival in NSCLC patients. Deregulation of miR-138/PDK1 cascade may be implicated in carcinogenesis and cancer progression of human NSCLC. More importantly, miR-138 and PDK1 may synergistically predict patients’ prognosis and their combination may represent a promising prognostic biomarker of human NSCLC.

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References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

    Article  PubMed  Google Scholar 

  2. López-González A, Millán PI, Cantos B, Provencio M. Surveillance of resected non-small cell lung cancer. Clin Transl Oncol. 2012;14:721–5.

    Article  PubMed  Google Scholar 

  3. Youlden DR, Cramb SM, Baade PD. The international epidemiology of lung cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3:819–31.

    Article  PubMed  Google Scholar 

  4. Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (NSCLC). J Thorac Dis. 2013;5:S389–96.

    PubMed  PubMed Central  Google Scholar 

  5. Filipits M, Pirker R. Predictive markers in the adjuvant therapy of non-small cell lung cancer. Lung Cancer. 2011;74:355–63.

    Article  PubMed  Google Scholar 

  6. Indovina P, Marcelli E, Maranta P, Tarro G. Lung cancer proteomics: recent advances in biomarker discovery. Int J Proteomics. 2011;2011:726869.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  PubMed  CAS  Google Scholar 

  8. Li PY, He FC, Zhou GQ. Association of human microRNA related genetic variations with cancer. Yi Chuan. 2011;33:870–8.

    Article  PubMed  CAS  Google Scholar 

  9. Zhang H, Li W, Nan F, Ren F, Wang H, Xu Y, Zhang F. MicroRNA expression profile of colon cancer stem-like cells in HT29 adenocarcinoma cell line. Biochem Biophys Res Commun. 2011;404:273–8.

    Article  PubMed  CAS  Google Scholar 

  10. de Krijger I, Mekenkamp LJ, Punt CJ, Nagtegaal ID. MicroRNAs in colorectal cancer metastasis. J Pathol. 2011;224:438–47.

    Article  PubMed  Google Scholar 

  11. Munker R, Calin GA. MicroRNA profiling in cancer. Clin Sci. 2011;121:141–58.

    Article  PubMed  CAS  Google Scholar 

  12. Baffa R, Fassan M, Volinia S, O’Hara B, Liu CG, Palazzo JP, et al. MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol. 2009;219:214–21.

    Article  PubMed  CAS  Google Scholar 

  13. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12:735–9.

    Article  PubMed  CAS  Google Scholar 

  14. Weber MJ. New human and mouse microRNA genes found by homology search. FEBS J. 2005;272:59–73.

    Article  PubMed  CAS  Google Scholar 

  15. Obernosterer G, Leuschner PJ, Alenius M, Martinez J. Post-transcriptional regulation of microRNA expression. RNA. 2006;12:1161–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Jin Y, Wang C, Liu X, Mu W, Chen Z, Yu D, Wang A, Dai Y, Zhou X. Molecular characterization of the microRNA-138-Fos-like antigen 1 (FOSL1) regulatory module in squamous cell carcinoma. J Biol Chem. 2011;286:40104–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Qiu S, Huang D, Yin D, Li F, Li X, Kung HF, Peng Y. Suppression of tumorigenicity by microRNA-138 through inhibition of EZH2-CDK4/6-pRb-E2F1 signal loop in glioblastoma multiforme. Biochim Biophys Acta. 2013;1832:1697–707.

    Article  PubMed  CAS  Google Scholar 

  18. Jin Y, Chen D, Cabay RJ, Wang A, Crowe DL, Zhou X. Role of microRNA-138 as a potential tumor suppressor in head and neck squamous cell carcinoma. Int Rev Cell Mol Biol. 2013;303:357–85.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A, Dai Y, Zhou X. MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J. 2011;440:23–31.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Wang Q, Zhong M, Liu W, Li J, Huang J, Zheng L. Alterations of microRNAs in cisplatin-resistant human non-small cell lung cancer cells (A549/DDP). Exp Lung Res. 2011;37:427–34.

    Article  PubMed  CAS  Google Scholar 

  21. Wang Q, Tang H, Yin S, Dong C. Downregulation of microRNA-138 enhances the proliferation, migration and invasion of cholangiocarcinoma cells through the upregulation of RhoC/p-ERK/MMP-2/MMP-9. Oncol Rep. 2013;29:2046–52.

    PubMed  CAS  Google Scholar 

  22. Yeh YM, Chuang CM, Chao KC, Wang LH. MicroRNA-138 suppresses ovarian cancer cell invasion and metastasis by targeting SOX4 and HIF-1α. Int J Cancer. 2013;133:867–78.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang H, Zhang H, Zhao M, Lv Z, Zhang X, Qin X, Wang H, Wang S, Su J, Lv X, Liu H, Du W, Zhou W, Chen X, Fei K. MiR-138 inhibits tumor growth through repression of EZH2 in non-small cell lung cancer. Cell Physiol Biochem. 2013;31:56–65.

    Article  PubMed  CAS  Google Scholar 

  24. Yang H, Tang Y, Guo W, Du Y, Wang Y, Li P, Zang W, Yin X, Wang H, Chu H, Zhang G, Zhao G. Up-regulation of microRNA-138 induce radiosensitization in lung cancer cells. Tumor Biol. 2014;35:6557–65.

  25. Ye XW, Yu H, Jin YK, Jing XT, Xu M, Wan ZF, Zhang XY. miR-138 inhibits proliferation by targeting 3-phosphoinositide-dependent protein kinase-1 in non-small cell lung cancer cells. Clin Respir J. 2014. doi:10.1111/crj.12100.

  26. Liu X, Lv XB, Wang XP, Sang Y, Xu S, Hu K, Wu M, Liang Y, Liu P, Tang J, Lu WH, Feng QS, Chen LZ, Qian CN, Bei JX, Kang T, Zeng YX. MiR-138 suppressed nasopharyngeal carcinoma growth and tumorigenesis by targeting the CCND1 oncogene. Cell Cycle. 2012;11:2495–506.

    Article  PubMed  CAS  Google Scholar 

  27. Long L, Huang G, Zhu H, Guo Y, Liu Y, Huo J. Down-regulation of miR-138 promotes colorectal cancer metastasis via directly targeting TWIST2. J Transl Med. 2013;11:275.

    Article  PubMed  Google Scholar 

  28. Medina JR. Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1. J Med Chem. 2013;56:2726–37.

    Article  PubMed  CAS  Google Scholar 

  29. Bayascas JR. PDK1: the major transducer of PI 3-kinase actions. Curr Top Microbiol Immunol. 2010;346:9–29.

    PubMed  CAS  Google Scholar 

  30. Raimondi C, Falasca M. Targeting PDK1 in cancer. Curr Med Chem. 2011;18:2763–9.

    Article  PubMed  CAS  Google Scholar 

  31. Li Y, Yang KJ, Park J. Multiple implications of 3-phosphoinositide-dependent protein kinase 1 in human cancer. World J Biol Chem. 2010;1:239–47.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bayascas JR, Leslie NR, Parsons R, Fleming S, Alessi DR. Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(±) mice. Curr Biol. 2005;15:1839–46.

    Article  PubMed  CAS  Google Scholar 

  33. Yu J, Chen KS, Li YN, Yang J, Zhao L. Silencing of PDK1 gene expression by RNA interference suppresses growth of esophageal cancer. Asian Pac J Cancer Prev. 2012;13:4147–51.

    Article  PubMed  Google Scholar 

  34. Liu Y, Wang J, Wu M, Wan W, Sun R, Yang D, Sun X, Ma D, Ying G, Zhang N. Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res. 2009;7:944–54.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Youguang Zheng.

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Han, L., Zhang, G., Zhang, N. et al. Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer. Med Oncol 31, 129 (2014). https://doi.org/10.1007/s12032-014-0129-y

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  • DOI: https://doi.org/10.1007/s12032-014-0129-y

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