微小RNA-216b在人胃腺癌中表达下调，并通过靶向癌基因HDAC8抑制细胞增殖和细胞周期进程。
MicroRNA-216b is Down-Regulated in Human Gastric Adenocarcinoma and Inhibits Proliferation and Cell Cycle Progression by Targeting Oncogene HDAC8.
作者信息
Wang Ying, Xu Po, Yao Jun, Yang Ruina, Shi Zhenguo, Zhu Xiaojuan, Feng Xiaoshan, Gao Shegan
机构信息
Oncology Department of the First Affiliated Hospital of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, Henan, 471003, China.
Urology Surgery Department of the First Affiliated Hospital of Henan University of Science and Technology, No. 24 Jinghua Road, Luoyang, Henan, 471003, China.
出版信息
Target Oncol. 2016 Apr;11(2):197-207. doi: 10.1007/s11523-015-0390-9.
PURPOSE
Accumulating evidence indicates that micro (mi)RNAs play a critical role in carcinogenesis and cancer progression; however, their role in the tumorigenesis of gastric adenocarcinoma remains unclear so the present study investigated this in gastric cancer (GC) tissues and cell lines.
METHODS
Human GC specimens (n = 57) and patient-paired non-cancerous specimens were obtained from patients at the First Affiliated Hospital, Henan University of Science and Technology. The AGS and GC9811 gastric cancer cell lines were also used. Expression levels of miR-216b and HDAC8 were examined by quantitative real-time PCR and the expression of HDAC8 was also examined by Western blotting and immunohistochemistry assay. The cell cycle progression was determined by FACS. MiR-216b inhibitor, mimics, and siRNA-HDAC8 transfections were performed to study the loss and gain of function.
RESULTS
We reported a significantly decreased expression of miR-216b in GC clinical specimens compared with paired non-cancerous tissues. We also observed a significant down-regulation of miR-216b expression in GC cell lines AGS and GC9811 (p < 0.0001). The introduction of miR-216b suppressed GC cell proliferation and cell cycle progression by targeting HDAC8, an oncogene shown to promote malignant tumor development with a potential miR-216b binding site in its 3' untranslated region. HDAC8 expression was shown to be significantly increased in AGS and GC9811 cell lines (p < 0.0001) and GC tissues compared with controls. Moreover, HDAC8 inhibition suppressed cell cycle progression compared with control groups (22 % ± 1.6 % vs 34 % ± 2.1), indicating that HDAC8 may function as an oncogene in the development of GC. Furthermore, HDAC8 expression was negatively correlated (p < 0.0001), while miR-216b expression was positively correlated with the clinical outcome of GC patients (p < 0.0001).
DISCUSSION
Our data suggest that miR-216b functions as a tumor suppressor in human GC by, at least partially, targeting HDAC8.
目的
越来越多的证据表明，微小（mi）RNA在致癌作用和癌症进展中起关键作用；然而，它们在胃腺癌肿瘤发生中的作用仍不清楚，因此本研究在胃癌（GC）组织和细胞系中对此进行了调查。
方法
从河南科技大学第一附属医院的患者中获取人GC标本（n = 57）和配对的癌旁标本。还使用了AGS和GC9811胃癌细胞系。通过定量实时PCR检测miR-216b和HDAC8的表达水平，并通过蛋白质印迹法和免疫组织化学分析检测HDAC8的表达。通过流式细胞术确定细胞周期进程。进行miR-216b抑制剂、模拟物和siRNA-HDAC8转染以研究功能的丧失和获得。
结果
我们报道，与配对的癌旁组织相比，GC临床标本中miR-216b的表达显著降低。我们还观察到在GC细胞系AGS和GC9811中miR-216b表达显著下调（p < 0.0001）。通过靶向HDAC8，miR-216b的导入抑制了GC细胞增殖和细胞周期进程，HDAC8是一种致癌基因，在其3'非翻译区具有潜在的miR-216b结合位点，可促进恶性肿瘤发展。与对照组相比，HDAC8在AGS和GC9811细胞系（p < 0.0001）以及GC组织中的表达显著增加。此外，与对照组相比，HDAC8抑制作用抑制了细胞周期进程（22% ± 1.6%对34% ± 2.1%），表明HDAC8可能在GC发展中作为致癌基因发挥作用。此外，HDAC8表达呈负相关（p < 0.0001），而miR-216b表达与GC患者的临床结局呈正相关（p < 0.0001）。
讨论
我们的数据表明，miR-216b至少部分通过靶向HDAC8在人GC中发挥肿瘤抑制作用。
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