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      MiR‐335‐5p restores cisplatin sensitivity in ovarian cancer cells through targeting BCL2L2

      research-article
      1 , , 2 , 3
      Cancer Medicine
      John Wiley and Sons Inc.
      BCL2L2, cisplatin, miR‐335‐5p, ovarian cancer

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          Abstract

          Objective

          Our study was designed to explore the association miR‐335‐5p and BCL2L2 and to investigate the influence of miR‐335‐5p/ BCL2L2 axis on cisplatin‐resistant ovarian cancer cells.

          Methods

          Microarray analysis was used to determine differentially expressed microRNAs in primary and cisplatin‐resistant A2780 cells. Cell function experiments were conducted to investigate the effect of miR‐335‐5p on the cisplatin sensitivity of A2780 cells. The targeted relationship between BCL2L2 mRNA and miR‐335‐5p was validated through luciferase assay. Tumor xenograft was performed to confirm the function of miR‐335‐5p in restoring the cisplatin sensitivity of the ovarian cancer cells.

          Results

          MiR‐335‐5p was lowly expressed in cisplatin‐resistant A2780 cells. Overexpression of miR‐335‐5p reduced cell survival and enhanced cisplatin‐induced cell apoptosis. BCL2L2 mRNA was a target of miR‐335‐5p, and silencing of BCL2L2 showed the similar results on the cell viability as miR‐335‐5p overexpression.

          Conclusion

          Upregulation of miR‐335‐5p expression enhanced the cisplatin sensitivity of ovarian cancer cells through suppressing BCL2L2, suggesting the potential of miR‐335‐5p/ BCL2L2 axis as a therapeutic target for the cisplatin resistance of patients with ovarian cancer.

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          Most cited references16

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          Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor.

          APO-1 (Fas/CD95), a member of the tumor necrosis factor receptor superfamily, induces apoptosis upon receptor oligomerization. In a search to identify intracellular signaling molecules coupling to oligomerized APO-1, several cytotoxicity-dependent APO-1-associated proteins (CAP) were immunoprecipitated from the apoptosis-sensitive human leukemic T cell line HUT78 and the lymphoblastoid B cell line SKW6.4. CAP1-3 (27-29 kDa) and CAP4 (55 kDa), instantly detectable after the crosslinking of APO-1, were associated only with aggregated (the signaling form of APO-1) and not with monomeric APO-1. CAP1 and CAP2 were identified as serine phosphorylated MORT1/FADD. The association of CAP1-4 with APO-1 was not observed with C-terminally truncated non-signaling APO-1. In addition, CAP1 and CAP2 did not associate with an APO-1 cytoplasmic tail carrying the lprcg amino acid replacement. Moreover, no APO-1-CAP association was found in the APO-1+, anti-APO-1-resistant pre-B cell line Boe. Our data suggest that in vivo CAP1-4 are the APO-1 apoptosis-transducing molecules.
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            Role of microRNAs in drug-resistant ovarian cancer cells.

            Chemotherapy is the preferred therapeutic approach for the therapy of advanced ovarian cancer, but a successful long-term treatment is prevented by the development of drug resistance. Recent works have underlined the involvement of non-coding RNAs, microRNAs (miRNAs) in cancer development, with several conjectures regarding their possible involvement in the evolution of drug resistance. This work was aimed to identify selected microRNAs involved in the development of chemoresistance in ovarian cancer. High-throughput analysis of the miRNA profile in a panel of paclitaxel- (A2780TAX, A2780TC1 and A2780TC3) and cisplatin-resistant (A2780CIS) cells was assessed using a microarray platform and subsequent validation with qPCR and Northern blots. Downstream target validation was performed for miR-130a and the target M-CSF.] Six miRNAs (let-7e, miR-30c, miR-125b, miR-130a and miR-335) were always diversely expressed in all the resistant cell lines. Let-7e was upregulated in A2780TAX cells, while it was downregulated in the other resistant cell lines. The opposite phenomenon was obtained for miR-125b, which was downregulated in A2780TAX and upregulated in the other cell lines. The miR-30c, miR-130a and miR-335 were downregulated in all the resistant cell lines, thereby suggesting a direct involvement in the development of chemoresistance. Finally downstream target validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a known resistance factor for ovarian cancer. Our results indicate that ovarian cancer drug resistance is associated with a distinct miRNA fingerprint, and miRNA microarrays could represent a prognostic tool to monitor the chemotherapy outcome.
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              Bcl2 family proteins in carcinogenesis and the treatment of cancer.

              Deregulation of Bcl2 family members is a frequent feature of human malignant diseases and causal for therapy resistance. A number of studies have recently shed light onto the role of pro- and anti-apoptotic Bcl2 family members in tumour-pathogenesis and in mediating the effects of classical as well as novel front-line anticancer agents, allowing the development of more efficient and more precisely targeted treatment regimens. Most excitingly, recent progress in our understanding of how Bcl2-like proteins maintain or perturb mitochondrial integrity has finally enabled the development of rational-design based anticancer therapies that directly target Bcl2 regulated events at the level of mitochondria. This review aims to give an overview on the most recent findings on the role of the Bcl2 family in tumour development in model systems of cancer, to relate these findings with observations made in human pathologies and drug-action.
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                Author and article information

                Contributors
                bizhangliping@126.com
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                17 July 2018
                September 2018
                : 7
                : 9 ( doiID: 10.1002/cam4.2018.7.issue-9 )
                : 4598-4609
                Affiliations
                [ 1 ] Department of Gynecological Affiliated Tumor Hospital of Zhengzhou University Henan Provincial Cancer Hospital Zhengzhou China
                [ 2 ] Department of Gynecological Ward 2 People's Hospital of Rizhao Rizhao China
                [ 3 ] Department of Gynecological People's Hospital of Shandong Linyi Economic and Technological Development Zone Linyi China
                Author notes
                [*] [* ] Correspondence: Ruonan Liu, Department of Gynecological, Affiliated Tumor Hospital of Zhengzhou University, Henan Provincial Cancer Hospital, No. 127 Dongming Road, Zhengzhou 450008, Henan, China ( bizhangliping@ 123456126.com ).
                Author information
                http://orcid.org/0000-0002-7949-8969
                Article
                CAM41682
                10.1002/cam4.1682
                6143943
                30019389
                3e136cbe-6670-473b-a038-f7b4bceb38a7
                © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 January 2018
                : 07 June 2018
                : 22 June 2018
                Page count
                Figures: 6, Tables: 1, Pages: 12, Words: 4988
                Categories
                Original Research
                Cancer Biology
                Original Research
                Custom metadata
                2.0
                cam41682
                September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.9 mode:remove_FC converted:19.09.2018

                Oncology & Radiotherapy
                bcl2l2,cisplatin,mir‐335‐5p,ovarian cancer
                Oncology & Radiotherapy
                bcl2l2, cisplatin, mir‐335‐5p, ovarian cancer

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