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      • Record: found
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      Silencing of miR-193a-5p increases the chemosensitivity of prostate cancer cells to docetaxel

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          Abstract

          Background

          Docetaxel-based chemotherapy failure in advanced prostate carcinoma has partly been attributed to the resistance of prostate cancer (PC) cells to docetaxel-induced apoptosis. Hence, there is an urgent need to identify mechanisms of docetaxel chemoresistance and to develop new combination therapies.

          Methods

          miR-193a-5p level was evaluated by qPCR in prostate tissues and cell lines, and its expression in the tissues was also examined by in situ hybridization. PC cell line (PC3 cell) was transfected with miR-193a-5p mimic or its inhibitor, and then cell apoptosis and the expression of its downstream genes Bach2 and HO-1 were detected by TUNEL staining and Western blotting. Luciferase reporter assay was used to detect the effect of miR-193a-5p and Bach2 on HO-1 expression. Xenograft animal model was used to test the effect of miR-193a-5p and docetaxel on PC3 xenograft growth.

          Results

          miR-193a-5p was upregulated in PC tissues and PC cell lines, with significant suppression of PC3 cell apoptosis induced by oxidative stress. Mechanistically, miR-193a-5p suppressed the expression of Bach2, a repressor of the HO-1 gene, by directly targeting the Bach2 mRNA 3′-UTR. Docetaxel treatment modestly decreased Bach2 expression and increased HO-1 level in PC3 cells, whereas a modest increase of HO-1 facilitated docetaxel-induced apoptosis. Notably, docetaxel-induced miR-193a-5p upregulation, which in turn inhibits Bach2 expression and thus relieves Bach2 repression of HO-1 expression, partly counteracted docetaxel-induced apoptosis, as evidenced by the increased Bcl-2 and decreased Bax expression. Accordingly, silencing of miR-193a-5p enhanced sensitization of PC3 cells to docetaxel-induced apoptosis. Finally, depletion of miR-193a-5p significantly reduced PC xenograft growth in vivo.

          Conclusions

          Silencing of miR-193a-5p or blockade of the miR-193a-5p-Bach2-HO-1 pathway may be a novel therapeutic approach for castration-resistant PC.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-017-0649-3) contains supplementary material, which is available to authorized users.

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          Most cited references38

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          Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites

          Doron Betel, Anjali Koppal, Phaedra Agius … (2010)
          mirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.
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            Observer variation in immunohistochemical analysis of protein expression, time for a change?

            T Kirkegaard, J. Edwards, S. Tovey … (2006)
            Immunohistochemical analysis of protein expression is central to most clinical translational studies and defines patient treatment or selection criteria for novel drugs. Interobserver variation is rarely analysed despite recognition that this is a key area of potential inaccuracy. Therefore our aim was to examine observer variation and suggest the revision of current standards. We analysed inter- and intra-observer variation, by interclass correlation coefficient (ICCC) and kappa statistics, in 8661 samples. Intra-observer assessment of nuclear, cytoplasmic and membrane staining for seven proteins in 1323 samples resulted in an ICCC of 0.94 and a kappa-value of 0.787. Interobserver reproducibility, assessed on 28 proteins by seven observer pairs in 8661 carcinomas, gave an ICCC of 0.90 and a kappa-value of 0.70. No significant effect of either antibody or cellular compartmentalization was observed. We have demonstrated that ICCC is a consistent method to assess observer variation when a continuous scoring system is used, compared with kappa statistics, which depends on a categorical system. Given the importance of accurate assessment of protein expression in diagnostic and experimental medicine, we suggest raising thresholds for observer variation: ICCC of 0.7 should be regarded as the minimum acceptable standard, ICCC of 0.8 as good and ICCC of > or = 0.9 as excellent.
            Article 0 comments Cited 88 times – based on 0 reviews     Review now
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              Class III beta-tubulin expression predicts prostate tumor aggressiveness and patient response to docetaxel-based chemotherapy.

              Bernard Paule, Stéphane Terry, Ralph Buttyan … (2010)
              Expression of class III β-tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxane-based therapies for several human malignancies, but its use as a biomarker of tumor behavior in prostate cancer (PCa) remains largely unexplored. Here, we describe βIII-tubulin immunohistochemical staining patterns of prostate tumors obtained from a broad spectrum of PCa patients, some of whom subsequently received docetaxel therapy for castration-resistant PCa (CRPC). Elevated βIII-tubulin expression was significantly associated with tumor aggressiveness in PCa patients with presumed localized disease, as it was found to be an independent marker of biochemical recurrence after treatment. Additionally, βIII-tubulin expression in tumor cells was an independent predictor of lower overall survival for patients receiving docetaxel-based chemotherapy for CRPC. Manipulation of βIII-tubulin expression in human PCa cell lines using a human βIII-tubulin expression vector or βIII-tubulin small interfering RNA altered cell survival in response to docetaxel treatment in a manner that supports a role for βIII-tubulin expression as a mediator of PCa cell resistance to docetaxel therapy. Our findings suggest a role for βIII-tubulin as candidate theranostic biomarker to predict the response to docetaxel-based chemotherapy as well as to target for treatment of docetaxel-resistant CRPC. Copyright © 2010 AACR.
              Article 0 comments Cited 62 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yong Zhang: 86-311-6600-2992 , zhangyong89@sina.com
                Journal
                Journal ID (nlm-ta): J Exp Clin Cancer Res
                Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res
                Title: Journal of Experimental & Clinical Cancer Research : CR
                Publisher: BioMed Central (London )
                ISSN (Print): 0392-9078
                ISSN (Electronic): 1756-9966
                Publication date (Electronic): 8 December 2017
                Publication date PMC-release: 8 December 2017
                Publication date Collection: 2017
                Volume: 36
                Electronic Location Identifier: 178
                Affiliations
                [1 ]ISNI 0000 0004 1804 3009, GRID grid.452702.6, Department of Urology, , The Second Hospital of Hebei Medical University, ; 215 Heping West Road, Shijiazhuang, 050000 China
                [2 ]GRID grid.256883.2, Department of Biochemistry and Molecular Biology, , Ministry of Education of China, Hebei Medical University, ; No. 361 Zhongshan E Rd, Shijiazhuang, 050017 China
                [3 ]ISNI 0000 0004 1804 3009, GRID grid.452702.6, Department of Science and Technology, , The Second Hospital of Hebei Medical University, ; 215 Heping W Rd, Shijiazhuang, 050000 China
                [4 ]ISNI 0000 0004 1804 3009, GRID grid.452702.6, Department of Emergency Medicine, , The second hospital of Hebei Medical University, ; Shijiazhuang, Hebei 050000 China
                Article
                Publisher ID: 649
                DOI: 10.1186/s13046-017-0649-3
                PMC ID: 5721613
                PubMed ID: 29216925
                SO-VID: cf6b654c-8256-4742-821d-d13f78be0052
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 12 September 2017
                Date accepted : 21 November 2017
                Funding
                Funded by: The National Natural Science Foundation of China
                Award ID: 81672555
                Award ID: 81600237
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: mir-193a-5p,prostate cancer,docetaxel,chemoresistance,ho-1,bach2
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: mir-193a-5p, prostate cancer, docetaxel, chemoresistance, ho-1, bach2

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