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Biological Chemistry

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Volume 395, Issue 9


Loss of miR-378 in prostate cancer, a common regulator of KLK2 and KLK4, correlates with aggressive disease phenotype and predicts the short-term relapse of the patients

Margaritis Avgeris
  • Department of Biochemistry and Molecular Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Konstantinos Stravodimos
  • First Department of Urology, “Laiko” General Hospital, Medical School, University of Athens, Agiou Thoma 17, 115 27 Athens, Greece
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Andreas Scorilas
  • Corresponding author
  • Department of Biochemistry and Molecular Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-08-06 | DOI: https://doi.org/10.1515/hsz-2014-0150


A large number of prostate cancer (PCa) patients receive treatment without significant benefits, strengthening the need for accurate prognosis, which can be supported by the study of miRNAs. In silico specificity analysis was performed for the identification of miRNAs able to regulate KLK2 and KLK4 expression. Total RNA was extracted from prostate tissues obtained from PCa and benign prostate hyperplasia patients. Thereafter, RNA was polyadenylated and reverse transcribed to cDNA, which was used for qPCR analysis. miR-378 was predicted to target both KLK2 and KLK4 and downregulated levels detected in PCa patients (p=0.050). The reduction of miR-378 was correlated with higher Gleason score (p=0.018), larger diameter tumors (p=0.034), and elevated serum PSA (p=0.006). Regarding prognosis, miR-378 was able to improve risk stratification according to Gleason score or tumor stage, while higher risk to recur highlighted for the patients expressing lower miR-378 levels. Finally, the loss of miR-378 was able to predict the short-term relapse of ‘high’- and ‘very high’-recurrence-risk patients, independent of Gleason score, tumor stage, PSA, and age as indicated by Kaplan-Meier survival curves (p=0.030) and multivariate Cox regression analysis (p=0.018). In conclusion, loss of miR-378 expression increases the risk for PCa progression and relapse, despite active treatment.

This article offers supplementary material which is provided at the end of the article.

Keywords: kallikrein-related peptidase; KLK; miR-378a; miR-422a; molecular tumor markers; prostate tumors


  • Andriole, G.L., Crawford, E.D., Grubb, R.L., 3rd, Buys, S.S., Chia, D., Church, T.R., Fouad, M.N., Gelmann, E.P., Kvale, P.A., Reding, D.J., et al. (2009). Mortality results from a randomized prostate-cancer screening trial. N. Engl. J. Med. 360, 1310–1319.Google Scholar

  • Avgeris, M., Mavridis, K., and Scorilas, A. (2010). Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies. Biol. Chem. 391, 505–511.Web of ScienceGoogle Scholar

  • Avgeris, M., Stravodimos, K., and Scorilas, A. (2011). Kallikrein-related peptidase 4 gene (KLK4) in prostate tumors: quantitative expression analysis and evaluation of its clinical significance. Prostate 71, 1780–1789.Web of ScienceGoogle Scholar

  • Avgeris, M., Mavridis, K., and Scorilas, A. (2012). Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance. Biol. Chem. 393, 301–317.Web of ScienceGoogle Scholar

  • Avgeris, M., Stravodimos, K., Fragoulis, E.G., and Scorilas, A. (2013). The loss of the tumour-suppressor miR-145 results in the shorter disease-free survival of prostate cancer patients. Br. J. Cancer 108, 2573–2581.Google Scholar

  • Bartel, D.P. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297.Web of ScienceGoogle Scholar

  • Bartels, C.L. and Tsongalis, G.J. (2009). MicroRNAs: novel biomarkers for human cancer. Clin. Chem. 55, 623–631.Google Scholar

  • Borgono, C.A., Michael, I.P., and Diamandis, E.P. (2004). Human tissue kallikreins: physiologic roles and applications in cancer. Mol. Cancer Res. 2, 257–280.Google Scholar

  • Calin, G.A. and Croce, C.M. (2006). MicroRNA signatures in human cancers. Nat. Rev. Cancer 6, 857–866.PubMedCrossrefGoogle Scholar

  • Chen, L.T., Xu, S.D., Xu, H., Zhang, J.F., Ning, J.F., and Wang, S.F. (2012). MicroRNA-378 is associated with non-small cell lung cancer brain metastasis by promoting cell migration, invasion and tumor angiogenesis. Med. Oncol. 29, 1673–1680.Web of ScienceGoogle Scholar

  • Chow, T.F., Crow, M., Earle, T., El-Said, H., Diamandis, E.P., and Yousef, G.M. (2008). Kallikreins as microRNA targets: an in silico and experimental-based analysis. Biol. Chem. 389, 731–738.Web of ScienceGoogle Scholar

  • Darson, M.F., Pacelli, A., Roche, P., Rittenhouse, H.G., Wolfert, R.L., Young, C.Y., Klee, G.G., Tindall, D.J., and Bostwick, D.G. (1997). Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 49, 857–862.Google Scholar

  • Fendler, A., Stephan, C., Yousef, G.M., and Jung, K. (2011). MicroRNAs as regulators of signal transduction in urological tumors. Clin. Chem. 57, 954–968.Web of ScienceGoogle Scholar

  • Feng, M., Li, Z., Aau, M., Wong, C.H., Yang, X., and Yu, Q. (2011). Myc/miR-378/TOB2/cyclin D1 functional module regulates oncogenic transformation. Oncogene 30, 2242–2251.Google Scholar

  • Freedland, S.J. (2011). Screening, risk assessment, and the approach to therapy in patients with prostate cancer. Cancer 117, 1123–1135.Google Scholar

  • Ganesan, J., Ramanujam, D., Sassi, Y., Ahles, A., Jentzsch, C., Werfel, S., Leierseder, S., Loyer, X., Giacca, M., Zentilin, L., et al. (2013). MiR-378 controls cardiac hypertrophy by combined repression of mitogen-activated protein kinase pathway factors. Circulation 127, 2097–2106.Web of ScienceGoogle Scholar

  • Herrala, A.M., Porvari, K.S., Kyllonen, A.P., and Vihko, P.T. (2001). Comparison of human prostate specific glandular kallikrein 2 and prostate specific antigen gene expression in prostate with gene amplification and overexpression of prostate specific glandular kallikrein 2 in tumor tissue. Cancer 92, 2975–2984.Google Scholar

  • Klokk, T.I., Kilander, A., Xi, Z., Waehre, H., Risberg, B., Danielsen, H.E., and Saatcioglu, F. (2007). Kallikrein 4 is a proliferative factor that is overexpressed in prostate cancer. Cancer Res. 67, 5221–5230.Web of ScienceGoogle Scholar

  • Knezevic, I., Patel, A., Sundaresan, N.R., Gupta, M.P., Solaro, R.J., Nagalingam, R.S., and Gupta, M. (2012). A novel cardiomyocyte-enriched microRNA, miR-378, targets insulin-like growth factor 1 receptor: implications in postnatal cardiac remodeling and cell survival. J. Biol. Chem. 287, 12913–12926.Web of ScienceGoogle Scholar

  • Larne, O., Edsjo, A., Bjartell, A., and Ceder, Y. (2009). Development of a miRNA assay for prostate cancer detection. Eur. Urol. Suppl. 8, S316.Google Scholar

  • Larne, O., Martens-Uzunova, E., Hagman, Z., Edsjo, A., Lippolis, G., den Berg, M.S., Bjartell, A., Jenster, G., and Ceder, Y. (2013). miQ–a novel microRNA based diagnostic and prognostic tool for prostate cancer. Int. J. Cancer 132, 2867–2875.Google Scholar

  • Lawrence, M.G., Lai, J., and Clements, J.A. (2010). Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. Endocr. Rev. 31, 407–446.Web of ScienceGoogle Scholar

  • Lee, D.Y., Deng, Z., Wang, C.H., and Yang, B.B. (2007). MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression. Proc. Natl. Acad. Sci. USA 104, 20350–20355.Google Scholar

  • Lichner, Z., Fendler, A., Saleh, C., Nasser, A.N., Boles, D., Al-Haddad, S., Kupchak, P., Dharsee, M., Nuin, P.S., Evans, K.R., et al. (2013). MicroRNA signature helps distinguish early from late biochemical failure in prostate cancer. Clin. Chem. 59, 1595–1603.Web of ScienceGoogle Scholar

  • Martens-Uzunova, E.S., Jalava, S.E., Dits, N.F., van Leenders, G.J., Moller, S., Trapman, J., Bangma, C.H., Litman, T., Visakorpi, T., and Jenster, G. (2012). Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene 31, 978–991.Web of ScienceGoogle Scholar

  • Mavridis, K. and Scorilas, A. (2010). Prognostic value and biological role of the kallikrein-related peptidases in human malignancies. Future Oncol. 6, 269–285.Web of ScienceGoogle Scholar

  • Mavridis, K., Stravodimos, K., and Scorilas, A. (2013). Downregulation and prognostic performance of microRNA 224 expression in prostate cancer. Clin. Chem. 59, 261–269.Google Scholar

  • Mavridis, K., Avgeris, M., and Scorilas, A. (2014). Targeting kallikrein-related peptidases in prostate cancer. Exp. Opin. Ther. Targets 18, 365–383.Web of ScienceGoogle Scholar

  • Mohler, J., Bahnson, R.R., Boston, B., Busby, J.E., D’Amico, A., Eastham, J.A., Enke, C.A., George, D., Horwitz, E.M., Huben, R.P., et al. (2010). NCCN clinical practice guidelines in oncology: prostate cancer. J. Natl. Compr. Canc. Netw. 8, 162–200.Google Scholar

  • Nagalingam, R.S., Sundaresan, N.R., Gupta, M.P., Geenen, D.L., Solaro, R.J., and Gupta, M. (2013). A cardiac-enriched microRNA, miR-378, blocks cardiac hypertrophy by targeting Ras signaling. J. Biol. Chem. 288, 11216–11232.Web of ScienceGoogle Scholar

  • Pasic, M.D., Olkhov, E., Bapat, B., and Yousef, G.M. (2012). Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there. Biol. Chem. 393, 319–330.Google Scholar

  • Porkka, K.P., Pfeiffer, M.J., Waltering, K.K., Vessella, R.L., Tammela, T.L., and Visakorpi, T. (2007). MicroRNA expression profiling in prostate cancer. Cancer Res. 67, 6130–6135.Google Scholar

  • Schaefer, A., Jung, M., Mollenkopf, H.J., Wagner, I., Stephan, C., Jentzmik, F., Miller, K., Lein, M., Kristiansen, G., and Jung, K. (2010a). Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int. J. Cancer 126, 1166–1176.Google Scholar

  • Schaefer, A., Stephan, C., Busch, J., Yousef, G.M., and Jung, K. (2010b). Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors. Nat. Rev. Urol. 7, 286–297.Web of ScienceGoogle Scholar

  • Schroder, F.H., Hugosson, J., Roobol, M.J., Tammela, T.L., Ciatto, S., Nelen, V., Kwiatkowski, M., Lujan, M., Lilja, H., Zappa, M., et al. (2009). Screening and prostate-cancer mortality in a randomized European study. N. Engl. J. Med. 360, 1320–1328.Web of ScienceGoogle Scholar

  • Skrzypek, K., Tertil, M., Golda, S., Ciesla, M., Weglarczyk, K., Collet, G., Guichard, A., Kozakowska, M., Boczkowski, J., Was, H., et al. (2013). Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis. Antioxid. Redox Signal. 19, 644–660.Web of ScienceGoogle Scholar

  • Wach, S., Nolte, E., Szczyrba, J., Stohr, R., Hartmann, A., Orntoft, T., Dyrskjot, L., Eltze, E., Wieland, W., Keck, B., et al. (2012). MicroRNA profiles of prostate carcinoma detected by multiplatform microRNA screening. Int. J. Cancer 130, 611–621.Google Scholar

About the article

Corresponding author: Andreas Scorilas, Department of Biochemistry and Molecular Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece, e-mail:

Received: 2014-02-19

Accepted: 2014-07-03

Published Online: 2014-08-06

Published in Print: 2014-09-01

Citation Information: Biological Chemistry, Volume 395, Issue 9, Pages 1095–1104, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2014-0150.

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