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急性成人T细胞白血病患者中表达HBZ的细胞中DICER和一些微小RNA的表达受损。

Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients.

作者信息

Gazon Hélène, Belrose Gildas, Terol Marie, Meniane Jean-Come, Mesnard Jean-Michel, Césaire Raymond, Peloponese Jean-Marie

机构信息

CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France.

Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique.

出版信息

Oncotarget. 2016 May 24;7(21):30258-75. doi: 10.18632/oncotarget.7162.

DOI:10.18632/oncotarget.7162
PMID:26849145
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5058679/
Abstract

Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.

摘要

微小RNA（miRNA）是一类调控基因表达的非编码RNA，其在全球范围内的失调是人类肿瘤的一个共同特征。Yamagishi等人对成人T细胞白血病（ATL）细胞中的细胞miRNA进行分析，结果显示ATL细胞中96.7%的细胞miRNA表达大幅下降。然而，ATL细胞中调控miRNA表达的机制仍 largely未知。在本研究中，我们比较了先前描述的因Tax而过表达的12种miR的表达，以及miRNA生物合成途径的几个关键成分在不同表达HBZ的细胞系以及急性ATL患者的原代CD4（+）细胞中的表达。我们发现，在表达HBZ的细胞系以及急性ATL患者的新鲜CD4（+）细胞中，miRNA和Dicer1的表达均下调。通过定量逆转录聚合酶链反应（qRT-PCR）、蛋白质印迹分析和染色质免疫沉淀，我们发现Dicer转录受两种AP-1转录因子c-Jun和JunD调控。我们还证明，HBZ通过从近端启动子去除JunD来影响Dicer的表达。此外，我们发现，在1mM的治疗浓度下，常用于癌症治疗的组蛋白去乙酰化酶抑制剂丙戊酸（VPA）可挽救Dicer表达和miRNA成熟。这些结果可能为新联合疗法的临床研究提供理论依据，以努力改善急性ATL患者的治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/251af4d7316a/oncotarget-07-30258-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/389b3131a046/oncotarget-07-30258-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/983ec3d2de20/oncotarget-07-30258-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/afb81ba4da13/oncotarget-07-30258-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/251af4d7316a/oncotarget-07-30258-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/5e528d6d904e/oncotarget-07-30258-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/72d5bd9dace7/oncotarget-07-30258-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/5e4b97fbe44c/oncotarget-07-30258-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/132f073bdc8f/oncotarget-07-30258-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/8184cbab09f8/oncotarget-07-30258-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/5c75e5a97f02/oncotarget-07-30258-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/389b3131a046/oncotarget-07-30258-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/983ec3d2de20/oncotarget-07-30258-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/afb81ba4da13/oncotarget-07-30258-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5081/5058679/251af4d7316a/oncotarget-07-30258-g010.jpg

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