下调的 miR-148b 通过拯救 Ezrin 增加弥漫性大 B 细胞淋巴瘤细胞对 CHOP 的耐药性。
Down-regulated miR-148b increases resistance to CHOP in diffuse large B-cell lymphoma cells by rescuing Ezrin.
机构信息
Department of Haematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Haematology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
出版信息
Biomed Pharmacother. 2018 Oct;106:267-274. doi: 10.1016/j.biopha.2018.06.093. Epub 2018 Jun 28.
BACKGROUND
Aberrant microRNA (miRNAs) have recently been proposed as important regulators in acquiring resistance to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to establish the role of miR-148b in the development of CHOP resistance in DLBCL.
METHODS
The expression patterns of miR-148b, HDAC6, and Ezrin were detected in CHOP-resistant clinical specimens and a DLBCL cell line. miR-148b, HDAC6, and Ezrin in DLBCL cells were manipulated by cell transfection to explore the functional correlation between them. Cell viability was determined using a CCK-8 assay.
RESULTS
We found that miR-148b levels were markedly reduced and that the protein expressions of HDAC6 and Ezrin were increased in DLBCL CHOP-resistant clinical specimens and the cell line CRL2631/CHOP. Indeed, HDAC6 decreased the acetylation of histones H3 and H4 in the miR-148b promoter to inhibit miR-148b expression in DLBCL. Moreover, down-regulated miR-148b encouraged CHOP resistance in CRL2631 cells and miR-148b sensitized CRL2631 cells. We further revealed that Ezrin was negatively regulated by miR-148b and that the knockdown of Ezrin significantly attenuated CHOP resistance in CRL2631 cells induced by miR-148b silencing. MiR-148b also sensitized CRL2631/CHOP cell xenografts to CHOP in mice.
CONCLUSION
Our data indicated that the high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.
背景
异常的 microRNA（miRNA）最近被认为是弥漫性大 B 细胞淋巴瘤（DLBCL）获得环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）耐药性的重要调节因子。本研究旨在确定 miR-148b 在 DLBCL 中 CHOP 耐药性发展中的作用。
方法
检测 CHOP 耐药临床标本和 DLBCL 细胞系中 miR-148b、HDAC6 和 Ezrin 的表达模式。通过细胞转染来操纵 DLBCL 细胞中的 miR-148b、HDAC6 和 Ezrin，以探索它们之间的功能相关性。使用 CCK-8 测定法测定细胞活力。
结果
我们发现 miR-148b 水平在 DLBCL CHOP 耐药临床标本和细胞系 CRL2631/CHOP 中明显降低，HDAC6 和 Ezrin 的蛋白表达增加。事实上，HDAC6 通过降低 miR-148b 启动子上组蛋白 H3 和 H4 的乙酰化来抑制 DLBCL 中 miR-148b 的表达。此外，下调的 miR-148b 促进了 CRL2631 细胞的 CHOP 耐药性，而 miR-148b 使 CRL2631 细胞对 miR-148b 沉默诱导的 CHOP 更加敏感。我们进一步揭示 Ezrin 受 miR-148b 负调控，并且 Ezrin 的敲低显著减弱了 miR-148b 沉默诱导的 CRL2631 细胞的 CHOP 耐药性。miR-148b 还使 CRL2631/CHOP 细胞异种移植在小鼠中对 CHOP 更加敏感。
结论
我们的数据表明，高水平的 HDAC6 通过维持 miR-148b 启动子上组蛋白 H3 和 H4 的低乙酰化来抑制 miR-148b，从而挽救 Ezrin 的表达并促进 DLBCL 中的 CHOP 耐药性。
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